bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒11‒12
37 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia.
  2. How I treat refractory and relapsed acute myeloid leukemia.
  3. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.
  4. Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.
  5. Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.
  6. Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents.
  7. Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study.
  8. Causes and Consequences of Clonal Hematopoiesis.
  9. Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia.
  10. Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.
  11. Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome.
  12. CD61 identifies a superior population of aged murine HSCs and is required to preserve quiescence and self-renewal.
  13. What do atomic bomb survivors teach us about therapy-free remission in people with chronic myeloid leukaemia?
  14. Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline.
  15. Peripheral blood haploidentical hematopoietic cell transplantation for patients aged 70 years and over with acute myeloid leukemia or high-risk myelodysplastic syndrome.
  16. BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia.
  17. Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.
  18. Shikonin exerts an anti-leukemia effect against FLT3-ITD mutated acute myeloid leukemia cells via targeting FLT3 tyrosine kinase and its downstream pathways.
  19. Targeted Radiation Delivery Before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-Term Survivors.
  20. Hypomethylating agents (HMAs) show benefit in AML rather than in intermediate/high-risk MDS based on genetic mutations in epigenetic modification (EMMs): from a retrospective study.
  21. Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study.
  22. The RioK1 network determines p53 activity at multiple levels.
  23. Are We Ready For "Triplet" Therapy in Higher-Risk MDS?
  24. Editorial: Articles from the Special Issue on Metabolic control in hematopoietic homeostasis; Edited by Keisuke Ito.
  25. Clonal Hematopoiesis in Patients With Cancer: How Much Should We Care?
  26. Durable Responses and Survival in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients Receiving the Allogeneic Leukemia-derived Dendritic Cell Vaccine DCP-001.
  27. Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.
  28. The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling.
  29. Prospective Multi-Institutional Study of Eculizumab to Treat High-Risk Stem Cell Transplant Associated TMA.
  30. Tretinoin Enhances the Effects of Chemotherapy in Juvenile Myelomonocytic Leukemia Using an Ex Vivo Drug Sensitivity Assay.
  31. Germline MPL mutations may be a rare cause of "triple-negative" thrombocytosis.
  32. Epitope base editing: Non-malignant stem cells are going undercover.
  33. Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.
  34. Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function.
  35. High-dose cytarabine induction therapy and flow cytometric measurable residual disease monitoring for children with acute myeloid leukemia.
  36. Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40 years old - a secondary analysis of a CIBMTR database.
  37. Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma.
  1. Leukemia. 2023 Nov 07.
    PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia.
    Islam Alshamleh, Nina Kurrle, Philipp Makowka, Raj Bhayadia, Rahul Kumar, Sebastian Süsser, Marcel Seibert, Damian Ludig, Sebastian Wolf, Sebastian E Koschade, Karoline Stoschek, Johanna Kreitz, Dominik C Fuhrmann, Rosa Toenges, Marco Notaro, Federico Comoglio, Jan Jacob Schuringa, Tobias Berg, Bernhard Brüne, Daniela S Krause, Jan-Henning Klusmann, Thomas Oellerich, Frank Schnütgen, Harald Schwalbe, Hubert Serve.
      High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20-30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.
    DOI:  https://doi.org/10.1038/s41375-023-02041-5
  2. Blood. 2023 Nov 09. pii: blood.2023022481. [Epub ahead of print]
    How I treat refractory and relapsed acute myeloid leukemia.
    Felicitas R Thol, Hartmut Döhner, Arnold Ganser.
      The majority of patients with acute myeloid leukemia (AML) develops refractory/relapsed (R/R) disease even in the presence of novel and targeted therapies. Given the biological complexity of the disease and differences in front-line treatments, there are only approved therapies for subgroups of R/R AML and enrollment into clinical trials should be first priority. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative strategy for the majority of patients. Therapeutic approaches, including allogeneic HCT, triggered by the presence of measurable residual disease (MRD) have recently evolved to prevent overt hematological relapse. Salvage therapy with chemotherapy or targeted therapy is frequently given prior to HCT to reduce the leukemic burden. Gilteritinib is approved by the Food and Drug Administration (FDA) and European Medicines Agency for patients with relapsed FLT3 mutated AML, while targeted therapy for relapsed IDH1/2 mutated AML has only FDA approval. Patients who are refractory or relapse after azacitidine and venetoclax (AZA/VEN) have a dismal outcome. In this setting, even available targeted therapies have unsatisfactory results. Examples of ongoing developments include menin inhibitors, a targeted therapy for patients with mutated NPM1 or KMT2A rearrangements, antibodies targeting the macrophage immune checkpoint CD47 as well as triple combinations involving AZA/VEN. The latter cause significant myelosuppressive effects, which make it challenging to find the right schedule and dose.
    DOI:  https://doi.org/10.1182/blood.2023022481
  3. Leukemia. 2023 Nov 07.
    A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.
    Guillermo Garcia-Manero, Nikolai A Podoltsev, Megan Othus, John M Pagel, Jerald P Radich, Min Fang, David A Rizzieri, Guido Marcucci, Stephen A Strickland, Mark R Litzow, M Lynn Savoie, Bruno C Medeiros, Mikkael A Sekeres, Tara L Lin, Geoffrey L Uy, Bayard L Powell, Jonathan E Kolitz, Richard A Larson, Richard M Stone, David Claxton, James Essell, Selina M Luger, Sanjay R Mohan, Anna Moseley, Frederick R Appelbaum, Harry P Erba.
      Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).
    DOI:  https://doi.org/10.1038/s41375-023-02073-x
  4. Haematologica. 2023 Nov 09.
    Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.
    Danny V Jeyaraju, Maryam Alapa, Ann Polonskaia, Alberto Risueño, Prakash Subramanyam, Amit Anand, Kaushik Ghosh, Charalampos Kyriakopoulos, Daiane Hemerich, Rose Hurren, Xiaoming Wang, Marcela Gronda, Aarif Ahsan, Hsiling Chiu, Geethu Thomas, Evan F Lind, Daniel L Menezes, Aaron D Schimmer, Patrick R Hagner, Anita Gandhi, Anjan G Thakurta.
      Oral azacitidine (Oral-Aza; CC-486) treatment results in longer median overall survival (OS) (24.7 vs 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of Oral-Aza (14 days/28-day cycle) allows for low exposure of azacitidine for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of Oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of Oral-Aza/extended exposure to azacitidine through in vitro and in vivo modeling. In cell lines, extended exposure to azacitidine results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to azacitidine, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of azacitidine induces differentiation and depletes CD34+CD38- LSCs. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSCs. Overall, our pre-clinical work reveals novel mechanistic insights into oral-Aza and its ability to target leukemic stem cells.
    DOI:  https://doi.org/10.3324/haematol.2023.283437
  5. Blood Adv. 2023 Nov 07. pii: bloodadvances.2023011578. [Epub ahead of print]
    Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.
    Janghee Woo, Darlene Lu, Andrew Lewandowski, Huilei Xu, Pablo Serrano-Fernandez, Margaret Healey, Denise P Yates, Michael T Beste, Peter Libby, Paul M Ridker, David P Steensma.
      Canakinumab, a monoclonal antibody targeting pro-inflammatory cytokine interleukin (IL)-1β, improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using Somascan@ and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia compared to patients with CH mutations without anemia or without CH mutations. Compared to those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, pro-inflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical utility of IL-1β blockade and support further study of canakinumab in patients with concurrent anemia and CH mutations. The study was funded by Novartis Corporation, US and registered at clinicaltrials.gov (NCT01327846).
    DOI:  https://doi.org/10.1182/bloodadvances.2023011578
  6. Br J Haematol. 2023 Nov 10.
    Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents.
    Guillermo Montalban-Bravo, Elias Jabbour, Gautam Borthakur, Tapan Kadia, Farhad Ravandi, Kelly Chien, Naveen Pemmaraju, Danielle Hammond, Xiao Qin Dong, Xuelin Huang, Heather Schneider, Rosmy John, Rashmi Kanagal-Shamana, Sanam Loghavi, Hagop Kantarjian, Guillermo Garcia-Manero.
      Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.
    Keywords:  CMML; MDS; clinical trials; therapy
    DOI:  https://doi.org/10.1111/bjh.19193
  7. Bone Marrow Transplant. 2023 Nov 08.
    Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study.
    Dawn Maze, Murat O Arcasoy, Ryan Henrie, Sonia Cerquozzi, Rammurti Kamble, Samer Al-Hadidi, Abdulraheem Yacoub, Anurag K Singh, Mahmoud Elsawy, Shireen Sirhan, Elliot Smith, Curtis Marcoux, Auro Viswabandya, Andrew Daly, Hassan Sibai, Caroline McNamara, Yuliang Shi, Wei Xu, Katherine Lajkosz, Lynda Foltz, Vikas Gupta.
      Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF.
    DOI:  https://doi.org/10.1038/s41409-023-02146-6
  8. Blood. 2023 Nov 06. pii: blood.2023022222. [Epub ahead of print]
    Causes and Consequences of Clonal Hematopoiesis.
    Lachelle D Weeks, Benjamin L Ebert.
      Clonal hematopoiesis (CH) describes the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor for the development of blood cancers. Moreover, CH is associated with non-malignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Detection of specific somatic mutations in the peripheral blood, in coordination with blood count parameters, can powerfully predict the development of hematologic malignancies and overall mortality. In this review we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients presenting to hematology clinics with CH.
    DOI:  https://doi.org/10.1182/blood.2023022222
  9. Mol Cancer. 2023 Nov 06. 22(1): 177
    Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia.
    Ji Eun Shin, Soo-Hyun Kim, Mingyu Kong, Hwa-Ryeon Kim, Sungmin Yoon, Kyung-Mi Kee, Jung Ah Kim, Dong Hyeon Kim, So Yeon Park, Jae Hyung Park, Hongtae Kim, Kyoung Tai No, Han-Woong Lee, Heon Yung Gee, Seunghee Hong, Kun-Liang Guan, Jae-Seok Roe, Hyunbeom Lee, Dong-Wook Kim, Hyun Woo Park.
      BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.
    RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.
    CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.
    Keywords:  AML; Blast phase; CD36; CML; Cancer; Drug resistance; FLT3; Hippo-YAP/TAZ pathway; Midostaurin; Ponatinib
    DOI:  https://doi.org/10.1186/s12943-023-01837-4
  10. Leuk Res. 2023 Oct 31. pii: S0145-2126(23)00672-0. [Epub ahead of print]135 107407
    Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.
    Aditya Ravindra, Luna Acharya, Bradley Loeffler, Sarah Mott, Grerk Sutamtewagul, Prajwal Dhakal.
      Combining venetoclax with the hypomethylating agents azacitidine or decitabine has shown high complete response rates (60-70 %) in newly diagnosed (ND) acute myeloid leukemia (AML). However, studies addressing the efficacy of this approach in relapsed/refractory (R/R) AML remain limited. We conducted a retrospective analysis on patients treated with venetoclax-based therapy at a single institution. Objective response rates (ORR) and overall survival (OS) were assessed using logistic regression and Cox regression models, respectively. The total study population exhibited an ORR of 64 % with a complete remission at 34 %, complete remission with incomplete count recovery at 19%, and morphologic leukemia free state at 11 %. Patients with ND AML had a better ORR (71 %) compared to R/R AML (55 %), but the difference was not statistically significant. Median OS for the overall population was 14.4 months (range: 2-26 months). In the ND group, patients had a longer 6-month OS (82 % vs. 55 % in R/R AML), while both cohorts showed similar 12- and 24-month OS. Factors such as the hypomethylating agent chosen, adverse cytogenetics, TP53 mutations, prior hypomethylating agent use, and stem cell transplant status did not significantly affect ORR or OS. These findings support the effectiveness of venetoclax-based treatments in ND and R/R AML.
    Keywords:  Acute myeloid leukemia; Hypomethylating agents; Newly diagnosed; Refractory; Relapsed; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2023.107407
  11. Front Hematol. 2023 ;pii: 1235170. [Epub ahead of print]2
    Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome.
    Yaseswini Neelamraju, Evisa Gjini, Sagar Chhangawala, Hao Fan, Shuning He, Chang-Bin Jing, Ashley T Nguyen, Subhash Prajapati, Caroline Sheridan, Yariv Houvras, Ari Melnick, A Thomas Look, Francine E Garrett-Bakelman.
      Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (tet2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age.Methods: In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs).
    Results and discussion: A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in tet2m/m HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of tet2-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.
    Keywords:  DNA methylation; TET2; hematopoietic progenitors; myelodysplastic syndrome; zebrafish
    DOI:  https://doi.org/10.3389/frhem.2023.1235170
  12. Blood Adv. 2023 Nov 08. pii: bloodadvances.2023011585. [Epub ahead of print]
    CD61 identifies a superior population of aged murine HSCs and is required to preserve quiescence and self-renewal.
    Natalia Skinder, Irene Sanz Fernández, Albertien Dethmers-Ausema, Ellen Weersing, Gerald de Haan.
      Aging leads to a decline in function of hematopoietic stem cells (HSCs) and increases susceptibility to hematological disease. We found CD61 to be highly expressed in aged murine HSCs. Here we investigate the role of CD61 in identifying distinct subpopulations of aged HSCs and assess how expression of CD61 affects stem cell function. We show that HSCs with high expression of CD61 are functionality superior and retain self-renewal capacity in serial transplantations. In primary transplantations aged CD61High HSCs function similarly compared to young HSCs. CD61High HSCs are more quiescent compared to their CD61Low counterparts. We also show that in aged BM CD61High and CD61Low HSCs are transcriptomically distinct populations. Collectively, our research identifies CD61 as a key player in maintaining stem cell quiescence, ensuring the preservation of their functional integrity and potential during aging. Moreover, CD61 emerges as a marker to prospectively isolate a superior, highly dormant population of young and aged HSCs, making it a valuable tool both in fundamental and clinical research.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011585
  13. Leukemia. 2023 Nov 10.
    What do atomic bomb survivors teach us about therapy-free remission in people with chronic myeloid leukaemia?
    Tomas Radivoyevitch, Robert Peter Gale, Matt E Kalaycio.
      
    DOI:  https://doi.org/10.1038/s41375-023-02081-x
  14. Br J Haematol. 2023 Nov 06.
    Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline.
    BSH Committee
      
    Keywords:  diagnostic haematology; guideline; myelofibrosis; prognosis
    DOI:  https://doi.org/10.1111/bjh.19164
  15. Bone Marrow Transplant. 2023 Nov 03.
    Peripheral blood haploidentical hematopoietic cell transplantation for patients aged 70 years and over with acute myeloid leukemia or high-risk myelodysplastic syndrome.
    Samia Harbi, Louison Brac de la Perriere, Benjamin Bouchacourt, Sylvain Garciaz, Thomas Pagliardini, Boris Calmels, Maud Cecile, Anne-Charlotte Lefloch, Yosr Hicheri, Marie-Anne Hospital, Sabine Fürst, Claude Lemarie, Cécile Braticevic, Faezeh Legrand, Elena Bekrieva, Pierre-Jean Weiller, Christian Chabannon, Norbert Vey, Didier Blaise, Raynier Devillier.
      Haploidentical stem cell transplantation (Haplo-SCT) using non-myeloablative conditioning regimen (NMAC) has extended the feasibility of allogeneic transplantation, notably in older patients. However, there is few data specifically focusing on patients aged 70 years and over with AML and MDS. Thus the benefit of transplantation in this population is still debated. Here we report our single center experience of peripheral blood Haplo-SCT with NMAC and post-transplantation cyclophosphamide in AML and MDS patients aged 70 years and over. We analyzed 50 patients (27 AML, 23 MDS) with a median age of 72 years (70-77), 12/50 (24%) with active disease at Haplo-SCT. Cumulative incidence of grade 3-4 acute and moderate or severe chronic GVHD were 6% and 25%, respectively. Non-relapse mortality (NRM) at day +100 was 0%. NRM, relapse, PFS and OS at 3 years were 16%, 18%, 66%, and 69%, respectively. Among patients who were disease free at 2 years post Haplo-SCT, 88% are living without immunosuppressive treatment. Peripheral blood Haplo-SCT is feasible in selected AML/MDS patients over 70 years, without any early NRM. It produces long-term disease control and survival. Thus, age by itself should not be considered as a formal barrier to Haplo-SCT.
    DOI:  https://doi.org/10.1038/s41409-023-02134-w
  16. Leukemia. 2023 Nov 09.
    BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia.
    Ying Wu, Patricia M A Zehnle, Jovana Rajak, Naile Koleci, Geoffroy Andrieux, Lorena Gallego-Villar, Konrad Aumann, Melanie Boerries, Charlotte M Niemeyer, Christian Flotho, Sheila Bohler, Miriam Erlacher.
      Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.
    DOI:  https://doi.org/10.1038/s41375-023-02079-5
  17. Br J Haematol. 2023 Nov 08.
    Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.
    Nianci Chen, Jiajia Pan, Yile Zhou, Liping Mao, Yinjun Lou, Jiejing Qian, Gaixiang Xu, Juying Wei, De Zhou, Lihong Shou, Li Huang, Minchao Yan, Hui Zeng, Cuihua Fan, Gongqiang Wu, Weiying Feng, Hongyan Tong, Jie Jin, Huafeng Wang.
      Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.
    Keywords:  FMS-like tyrosine kinase 3 mutation; acute myeloid leukaemia; gilteritinib; relapsed/refractory
    DOI:  https://doi.org/10.1111/bjh.19182
  18. Acta Haematol. 2023 Nov 03.
    Shikonin exerts an anti-leukemia effect against FLT3-ITD mutated acute myeloid leukemia cells via targeting FLT3 tyrosine kinase and its downstream pathways.
    Mu-Nan Zhao, Long Su, Fei Song, Zhi-Feng Wei, Tian-Xue Qin, Yun-Wei Zhang, Wei Li, Su-Jun Gao.
      INTRODUCTION: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the anti-leukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo.METHODS: The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the anti-leukemia effect of SHK against FLT3-ITD mutated leukemia in vivo.
    RESULTS: After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutations. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.
    CONCLUSION: The findings of this study indicate that SHK is a promising drug for the treatment of FLT3-ITD mutated AML.
    DOI:  https://doi.org/10.1159/000534101
  19. Clin Cancer Res. 2023 Nov 08.
    Targeted Radiation Delivery Before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-Term Survivors.
    Johnnie J Orozco, Phuong T Vo, Ted A Gooley, Robyn L Haaf, Sally J Lundberg, Donald K Hamlinn, D Scott Wilbur, Manuela C Matesan, Darrell R Fisher, Ajay K Gopal, Damian J Green, John M Pagel, Brenda M Sandmaier.
      PURPOSE: Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase 1/2 study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML and ALL), or myelodysplastic syndrome (MDS) [ClinicalTrials.gov, NCT00589316].EXPERIMENTAL DESIGN: Patients received a tracer diagnostic dose before a therapeutic infusion of 131I-anti-CD45 to deliver escalating doses (12 to 26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was post-transplant CY plus tacrolimus and mycophenolate mofetil.
    RESULTS: Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9-20 %), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only two patients showing minimal residual disease (0.002 -1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% and 24% at 2 years, respectively. Point estimates of relapse and non-relapse mortality at 1 year were 56% and 12%, respectively.
    CONCLUSION: 131l-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1200
  20. Ann Hematol. 2023 Nov 06.
    Hypomethylating agents (HMAs) show benefit in AML rather than in intermediate/high-risk MDS based on genetic mutations in epigenetic modification (EMMs): from a retrospective study.
    Ruiqi Wang, Yuanyuan Xu, Bianhong Wang, Hong Wang, Mengzhen Wang, Yu Jing, Xiaoning Gao, Li Yu.
      Since HMAs were recommended for treatments in AML and MDS, we wondered whether HMAs could provide similar benefit to AML and intermediate/high-risk MDS under the direction of next-generation sequencing. Here we retrospectively analyzed the prognosis of 176 AML and 128 intermediate/high-risk MDS patients treated with HMAs or non-HMA regimens. For AML, HMAs regimen was related to better CR rate compared with non-HMA regimen in elder cohort, while the situation was the opposite in younger cohort. In consolidation phase, EMM (+) patients could benefit from HMAs regimen. Relapsed AML patients receiving HMAs regimen rather than non-HMA regimen had better post-relapse survival. Multivariate analysis identified HMA regimen as an independent prognostic factor for OS in EMM (+) cohort. For intermediate/high-risk MDS patients not undergoing HSCT, however, HMA regimen showed no survival advantage in EMM (+) cohort and was conversely associated with shorter survival in EMM (-) cohort compared with non-HMA regimen. And among those undergoing HSCT, HMA prior to HSCT predicted poor prognosis compared with upfront HSCT regardless of the existence of EMMs. Therefore, HMAs had better therapeutic value in AML rather than in intermediate/high-risk MDS based on EMMs.
    Keywords:  Acute myeloid leukemia; Hypomethylating agent; Mutations in epigenetic modification genes; Myelodysplastic syndrome
    DOI:  https://doi.org/10.1007/s00277-023-05438-5
  21. Blood Adv. 2023 Nov 07. pii: bloodadvances.2023011181. [Epub ahead of print]
    Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study.
    Saskia K Klein, Gerwin A Huls, Otto Visser, Hanneke C Kluin-Nelemans, Avinash G Dinmohamed.
      MDS/ MPN with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the myelodysplastic/myeloproliferative neoplasms is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/ MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (>65 years of age HR 1.85, P=0.001 and alloHSCT HR 0.51, P=0.039). As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011181
  22. Cell Death Discov. 2023 Nov 07. 9(1): 410
    The RioK1 network determines p53 activity at multiple levels.
    Michela Damizia, Gian Mario Moretta, Peter De Wulf.
      By responding to a host of adverse conditions, ranging from DNA damage to viral infection, transcription factor p53 supports genomic stability, cellular health, and survival. Not surprisingly, tumours across the cancer spectrum carry mutations in p53, misexpress the protein, or dysregulate its activity. Several signalling pathways, many of which comprise oncogenic proteins, converge upon p53 to control its stability and activity. We here present the conserved kinase/ATPase RioK1 as an upstream factor that determines p53 activity at the DNA, RNA, and protein levels. It achieves this task by integrating the regulatory events that act on p53 into a coherent response circuit. We will also discuss how RIOK1 overexpression represents an alternative mechanism for cancers to inactivate p53, and how targeting RioK1 could eradicate malignancies that are driven by a dysregulated RioK1-p53 network.
    DOI:  https://doi.org/10.1038/s41420-023-01704-7
  23. Clin Hematol Int. 2023 ;5(4): 88301
    Are We Ready For "Triplet" Therapy in Higher-Risk MDS?
    Andrew M Brunner, Uwe Platzbecker, Amy E DeZern, Amer M Zeidan.
      Higher-risk Myelodysplastic Syndromes/Neoplasms (MDS) represent an ongoing therapeutic challenge, with few effective therapies, many of which may have limited use in this older patient population often with considerations around comorbidities. Outside of transplant, azacitidine and decitabine remain the only disease-modifying therapies, and are palliative in nature. Recent interest has grown in extending combination chemotherapies used to treat acute myeloid leukemia (AML) to patients with MDS, including novel combination chemotherapy "doublets" and "triplets." In this review, we discuss considerations around combination chemotherapy in MDS, specifically as relates to study design, appropriate endpoints, supportive considerations, and how to integrate these into the current treatment paradigm. New therapies in MDS are desperately needed but also require considerations particular to this unique patient population.
    Keywords:  allogeneic transplant; azacitidine; combination chemotherapy; decitabine; myelodysplastic syndromes
    DOI:  https://doi.org/10.46989/001c.88301
  24. Exp Hematol. 2023 Nov 04. pii: S0301-472X(23)01759-9. [Epub ahead of print]
    Editorial: Articles from the Special Issue on Metabolic control in hematopoietic homeostasis; Edited by Keisuke Ito.
    Dr Ito Keisuke.
      
    DOI:  https://doi.org/10.1016/j.exphem.2023.11.001
  25. JCO Precis Oncol. 2023 Sep;7 e2300417
    Clonal Hematopoiesis in Patients With Cancer: How Much Should We Care?
    Aline Renneville, Elsa Bernard, Jean-Baptiste Micol.
      
    DOI:  https://doi.org/10.1200/PO.23.00417
  26. Hemasphere. 2023 Nov;7(11): e968
    Durable Responses and Survival in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients Receiving the Allogeneic Leukemia-derived Dendritic Cell Vaccine DCP-001.
    Luca L G Janssen, Theresia M Westers, Jeroen Rovers, Peter J M Valk, Jacqueline Cloos, Tanja D de Gruijl, Arjan A van de Loosdrecht.
      
    DOI:  https://doi.org/10.1097/HS9.0000000000000968
  27. Biomater Res. 2023 Nov 06. 27(1): 111
    Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.
    Dana M Alhattab, Ioannis Isaioglou, Salwa Alshehri, Zainab N Khan, Hepi H Susapto, Yanyan Li, Yara Marghani, Arwa A Alghuneim, Rubén Díaz-Rúa, Sherin Abdelrahman, Shuroug Al-Bihani, Farid Ahmed, Raed I Felimban, Heba Alkhatabi, Raed Alserihi, Malak Abedalthagafi, AlShaibani AlFadel, Abdalla Awidi, Adeel Gulzar Chaudhary, Jasmeen Merzaban, Charlotte A E Hauser.
      BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies.METHODS: To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells.
    RESULTS: The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse.
    CONCLUSIONS: Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments.
    Keywords:  3D bone marrow (niche-like) Disease model; 3D multicellular bioprinting; Acute Myeloid Leukemia; Ultrashort self-assembling peptide scaffolds; Whole transcriptome analysis
    DOI:  https://doi.org/10.1186/s40824-023-00457-9
  28. Front Oncol. 2023 ;13 1277453
    The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling.
    Kathrin Olschok, Bianca Altenburg, Marcelo A S de Toledo, Angela Maurer, Anne Abels, Fabian Beier, Deniz Gezer, Susanne Isfort, Katrin Paeschke, Tim H Brümmendorf, Martin Zenke, Nicolas Chatain, Steffen Koschmieder.
      Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient's clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient's primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1MPL and murine 32DMPL cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable.
    Keywords:   Myeloproliferative neoplasms (MPN); CALR mutations; JAK2V617F; imetelstat (GRN163L); induced pluripotent stem cells; myelofibrosis (MF); telomere length (TL)
    DOI:  https://doi.org/10.3389/fonc.2023.1277453
  29. Blood. 2023 Nov 09. pii: blood.2023022526. [Epub ahead of print]
    Prospective Multi-Institutional Study of Eculizumab to Treat High-Risk Stem Cell Transplant Associated TMA.
    Sonata Jodele, Christopher E Dandoy, Paibel Aguayo-Hiraldo, Adam Lane, Ashley Teusink-Cross, Anthony Sabulski, Kana Mizuno, Benjamin L Laskin, Jason Lawrence Freedman, Stella M Davies.
      High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS (NCT03518203). We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. High-risk TA-TMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS six-months after hrTMA diagnosis and one-year post-transplant survival. The eculizumab dosing regimen included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects with hrTMA had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (p<0.0001) six months after hrTMA diagnosis and 62% one year after-transplant. Eleven of fifteen survivors (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing regimen and real time TA-TMA biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy that can be initiated prior to organ injury. ClinicalTrials.gov (NCT03518203).
    DOI:  https://doi.org/10.1182/blood.2023022526
  30. JCO Precis Oncol. 2023 Sep;7 e2300302
    Tretinoin Enhances the Effects of Chemotherapy in Juvenile Myelomonocytic Leukemia Using an Ex Vivo Drug Sensitivity Assay.
    Elliot Stieglitz, Christine J Gu, Michelle Richardson, Ryosuke Kita, Marianne T Santaguida, Kamran A Ali, Debbie C Strachan, Anukriti Dhar, George Yam, Wade Anderson, Erica Anderson, Juwita Hübner, Sarah K Tasian, Mignon L Loh, Markus D Lacher.
      PURPOSE: Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities.METHODS: We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size.
    RESULTS: We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38+ cells increased from 7% (0.03%-25%; FLA) to 17% (0.3%-38%; FLA + TRET) or from 10% (0.2%-31%; AZA) to 51% (0.8%-88%; AZA + TRET).
    CONCLUSION: TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.
    DOI:  https://doi.org/10.1200/PO.23.00302
  31. Exp Hematol. 2023 Nov 06. pii: S0301-472X(23)01760-5. [Epub ahead of print]
    Germline MPL mutations may be a rare cause of "triple-negative" thrombocytosis.
    Oscar Borsani, Daniela Pietra, Ilaria Carola Casetti, Daniele Vanni, Giacomo Riccaboni, Silvia Catricalà, Bossi Grazia, Emanuela Boveri, Luca Arcaini, Elisa Rumi.
      Hereditary thrombocytosis (HT) are rare inherited disorders with clinical features resembling sporadic essential thrombocythemia. This study included 933 patients with persistent isolated thrombocytosis for whom secondary reactive causes were excluded. Of 933 patients screened, 567 were JAK2-mutated, 255 CALR-mutated, 41 MPL-mutated, 2 double-mutated and 68 triple-negative. Two MPL-mutated patients carried a germline non-canonical mutation located in exon 10: MPL W515* and MPL V501A. One triple-negative patients carried another germline non-canonical MPL mutation located outside exon 10: MPL R102P. As germline MPL mutations may underly HT, we recommend to screen patients with triple-negative isolated thrombocytosis for non-canonical MPL mutations. Although clear evidence concerning treatment of HT is still lacking, individuals with HT should probably not be given a cytoreductive treatment. Thus, a correct diagnosis is pivotal to avoid unnecessary treatments.
    Keywords:  MPL; hereditary; myeloproliferative; thrombocytosis
    DOI:  https://doi.org/10.1016/j.exphem.2023.10.005
  32. Cell Stem Cell. 2023 Nov 02. pii: S1934-5909(23)00330-2. [Epub ahead of print]30(11): 1400-1402
    Epitope base editing: Non-malignant stem cells are going undercover.
    Shayan Saniei, Elvin Wagenblast.
      Engineered hematopoietic stem cells can be shielded from targeted immunotherapy. Recently published in Nature, Casirati et al. utilized single-base editing of epitopes implicated in acute myeloid leukemia and healthy hematopoiesis to alter their antibody and chimeric antigen receptor (CAR) T recognition while preserving their ligand binding and enzymatic function.
    DOI:  https://doi.org/10.1016/j.stem.2023.09.009
  33. Nat Genet. 2023 Nov 06.
    Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.
    Simon N Stacey, Florian Zink, Gisli H Halldorsson, Lilja Stefansdottir, Sigurjon A Gudjonsson, Gudmundur Einarsson, Grimur Hjörleifsson, Thjodbjorg Eiriksdottir, Anna Helgadottir, Gyda Björnsdottir, Thorgeir E Thorgeirsson, Thorunn A Olafsdottir, Ingileif Jonsdottir, Solveig Gretarsdottir, Vinicius Tragante, Magnus K Magnusson, Hakon Jonsson, Julius Gudmundsson, Sigurgeir Olafsson, Hilma Holm, Daniel F Gudbjartsson, Patrick Sulem, Agnar Helgason, Unnur Thorsteinsdottir, Laufey Tryggvadottir, Thorunn Rafnar, Pall Melsted, Magnus Ö Ulfarsson, Brynjar Vidarsson, Gudmar Thorleifsson, Kari Stefansson.
      Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.
    DOI:  https://doi.org/10.1038/s41588-023-01555-z
  34. Cancer Discov. 2023 Nov 07.
    Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function.
    Nayan Jain, Zeguo Zhao, Richard P Koche, Chenling Antelope, Yosi Gozlan, Antonino Montalbano, David Brocks, Michael Lopez, Anton Dobrin, Yuzhe Shi, Gertrude Gunset, Theodoros Giavridis, Michel Sadelain.
      Suboptimal functional persistence limits the efficacy of adoptive T cell therapies. CD28-based chimeric antigen receptors (CARs) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall anti-tumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges. Transcriptional and genome accessibility profiling of repeatedly challenged CAR T cells shows improved expression and accessibility of memory transcription factors in SUV39H1-edited CAR T cells. SUV39H1 editing also reduces expression of inhibitory receptors and limits exhaustion in CAR T cells that have undergone multiple rechallenges. Our findings thus demonstrate the potential of epigenetic programming of CAR T cells to balance their function and persistence for improved adoptive cell therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1319
  35. Leukemia. 2023 Nov 06.
    High-dose cytarabine induction therapy and flow cytometric measurable residual disease monitoring for children with acute myeloid leukemia.
    Daisuke Tomizawa, Jun Matsubayashi, Shotaro Iwamoto, Hidefumi Hiramatsu, Daisuke Hasegawa, Hiroshi Moritake, Daiichiro Hasegawa, Kiminori Terui, Asahito Hama, Shin-Ichi Tsujimoto, Nobutaka Kiyokawa, Hayato Miyachi, Takao Deguchi, Yoshiko Hashii, Yuka Iijima-Yamashita, Tomohiko Taki, Yasushi Noguchi, Kazutoshi Koike, Katsuyoshi Koh, Yuki Yuza, Akiko Moriya Saito, Keizo Horibe, Takashi Taga, Shiro Tanaka, Souichi Adachi.
      
    DOI:  https://doi.org/10.1038/s41375-023-02075-9
  36. Ann Hematol. 2023 Nov 09.
    Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40 years old - a secondary analysis of a CIBMTR database.
    Irtis de Oliveira Fernandes Junior, Leonardo Javier Arcuri.
      Few studies have addressed the role of reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens in older adults with Philadelphia acute lymphoblastic leukemia (Ph + ALL). The objective of this current study was to compare the outcomes of RIC/NMA versus TBI-based myeloablative (MAC) regimens in Ph + ALL patients older than 40 years old who underwent hematopoietic cell transplantation (HCT) in CR1. We used a freely available database from the CIBMTR. Transplants were performed between 2013 and 2017. With a median follow-up of 37.6 months, we have included 629 patients. We used propensity score weighting. Three-year OSs were 64% in the TBI-MAC group and 66% in the RIC/NMA group. OS was not different (HR = 0.92; p = 0.69). Three-year relapse incidences were 21.6% and 27.6% in the TBI-MAC and RIC/NMA groups. RIC/NMA was not associated with an increase in relapse rate (HR 1.02; p = 0.91). Three-year NRMs were 24.3% in the TBI-MAC group and 20.3% in the RIC/NMA group. RIC/NMA was not associated with superior NRM (HR 0.88; p = 0.57). In summary, we have shown that RIC/NMA regimens achieve outcomes comparable to TBI-based MAC in Ph+ ALL older patients in CR1 who may tolerate a TBI-based MAC regimen.
    Keywords:  Acute lymphoblastic leukemia; Allogeneic hematopoietic cell transplantation; CIBMTR; Myeloablative conditioning regimen; Philadelphia-positive acute lymphoblastic leukemia; Reduced-intensity conditioning regimen
    DOI:  https://doi.org/10.1007/s00277-023-05532-8
  37. Haematologica. 2023 Nov 09.
    Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma.
    Stien De Coninck, Renate De Smedt, Beatrice Lintermans, Lindy Reunes, Hansen J Kosasih, Alexandra Reekmans, Lauren M Brown, Nadine Van Roy, Bruno Palhais, Juliette Roels, Malaika Van der Linden, Jo Van Dorpe, Panagiotis Ntziachristos, Frederik W Van Delft, Marc R Mansour, Tim Pieters, Tim Lammens, Barbara De Moerloose, Charles E De Bock, Steven Goossens, Pieter Van Vlierberghe.
      T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematological malignancies. Current treatment consists of intensive chemotherapy, leading to 80% overall survival but are associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL and that screening T-ALL/TLBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.
    DOI:  https://doi.org/10.3324/haematol.2023.283981
This page is being maintained by Thomas Krichel. It was last updated on 2023‒11‒12 at 7:50.