bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024‒07‒21
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. PHF6 suppresses self-renewal of leukemic stem cells in AML.
  2. FLT3/CD99 Bispecific antibody-based nanoparticles (BiAbs) for Acute Myeloid Leukemia.
  3. Molecular relapse after first-line intensive therapy in patients with CBF or NPM1-mutated acute myeloid leukemia - a FILO study.
  4. Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.
  5. Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?
  6. Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.
  7. Clinical and molecular characteristics of extramedullary acute myeloid leukemias.
  8. Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia.
  9. Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.
  10. Real-world effectiveness of first-line azacitidine or decitabine with or without venetoclax in acute myeloid leukemia patients unfit for intensive therapy.
  11. Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.
  12. Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.
  13. HOXA9 Regulome and Pharmacological Interventions in Leukemia.
  14. Myeloid neoplasms arising after methotrexate therapy for autoimmune rheumatological diseases do not exhibit poor-risk molecular features.
  15. Clinical utility of investigations in triple-negative thrombocytosis: A real-world, multicentre evaluation of UK practice.
  16. Hope for Motherhood: Pregnancy After Allogeneic Hematopoietic Cell Transplantation - a National Multicenter Study.
  17. Unrelated donor transplantation with post-transplant cyclophosphamide versus ATG for myelodysplastic neoplasms.
  18. Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score.
  19. MLL-AF9 regulates transcriptional initiation in mixed lineage leukemic cells.
  20. Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation.
  21. Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis.
  22. Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors.
  23. Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.
  24. Mobilization dynamics of bone marrow hematopoietic stem cells during hematopoietic regeneration.
  25. Novel Vpx virus-like particles to improve cytarabine treatment response against acute myeloid leukemia.
  26. FBXL6 is a vulnerability in AML and unmasks proteolytic cleavage as a major experimental pitfall in myeloid cells.
  27. Using Mendelian Randomisation to search for modifiable risk factors influencing the development of clonal haematopoiesis.
  28. Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms.
  29. Interplay between donor age and HLA-DP matching in 10/10 HLA-matched unrelated donor HCT.
  30. In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.
  31. Clonal inactivation of TERT impairs stem cell competition.
  32. Chronic graft-versus-host disease: Unresolved complication or ancient history?
  1. Leukemia. 2024 Jul 14.
    PHF6 suppresses self-renewal of leukemic stem cells in AML.
    Sapana S Jalnapurkar, Aishwarya S Pawar, Subin S George, Charles Antony, Patrick Somers, Jason Grana, Victoria K Feist, Sandeep Gurbuxani, Vikram R Paralkar.
      Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the "LIC-e" (leukemia initiating cells enriched) population. We find that Phf6 loss expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.
    DOI:  https://doi.org/10.1038/s41375-024-02340-5
  2. Cancer Res Commun. 2024 Jul 15.
    FLT3/CD99 Bispecific antibody-based nanoparticles (BiAbs) for Acute Myeloid Leukemia.
    Atham Ali, Alvin Phan, Vijaya Vaikari, Mincheol Park, Mateusz Pospiech, Ryan Chu, Yiting Meng, John A MacKay, Houda Alachkar.
      CD99 is a receptor that is significantly upregulated in AML. FLT3-ITD AML exhibits even higher levels of CD99 expression. Our group previously employed a novel peptide platform technology called elastin-like polypeptides and fused it with single-chain antibodies (scFv) capable of binding to FLT3 (FLT3-A192), or CD99 (CD99-A192). Targeting either FLT3 or CD99 using FLT3-A192 or CD99-A192 led to AML cell death and reduced leukemia burden in AML mouse models. Here, we report on the development of a novel co-assembled construct that is capable to binding both CD99 and FLT3 and the antileukemia activity of the bispecific construct in FLT3-ITD AML preclinical models. This dual-targeting Co-Assembled formulation exhibits cytotoxic effects on AML cells (AML cell lines and primary blasts) and reduced leukemia burden and prolonged survival in FLT3-ITD AML mouse models. Altogether, this study demonstrates the potential of an innovative therapeutic strategy that targets both FLT3 and CD99 in FLT3-ITD AML.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0096
  3. Leukemia. 2024 Jul 17.
    Molecular relapse after first-line intensive therapy in patients with CBF or NPM1-mutated acute myeloid leukemia - a FILO study.
    Corentin Orvain, Sarah Bertoli, Pierre Peterlin, Yohann Desbrosses, Pierre-Yves Dumas, Alexandre Iat, Marie-Anne Hospital, Martin Carre, Emmanuelle Tavernier, Jérémie Riou, Anne Bouvier, Audrey Bidet, Sylvie Tondeur, Florian Renosi, Marie-Joelle Mozziconacci, Pascale Flandrin-Gresta, Bérengère Dadone-Montaudié, Eric Delabesse, Arnaud Pigneux, Mathilde Hunault-Berger, Christian Recher.
      Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved first complete remission (CR) to detect morphologic relapse and drive preemptive therapy. How to best manage these patients is unknown. We retrospectively analyzed 303 patients with CBF and NPM1-mutated AML, aged 18-60 years, without allogeneic hematopoietic cell transplantation (HCT) in first CR, with molecular monitoring after first-line intensive therapy. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse (53 received preemptive therapy and 42 progressed to morphologic relapse at salvage therapy), and 55 (18%) had upfront morphologic relapse. Patients who received preemptive therapy had higher OS than those who received salvage therapy after having progressed from molecular to morphologic relapse and those with upfront morphologic relapse (three-year OS: 78% vs. 51% vs. 51%, respectively, P = 0.01). Preemptive therapy included upfront allogeneic HCT (n = 19), intensive chemotherapy (n = 21), and non-intensive therapy (n = 13; three-year OS: 92% vs. 79% vs. 58%, respectively, P = 0.09). Although not definitive due to the non-randomized allocation of patients to different treatment strategies at relapse, our study suggests that molecular monitoring should be considered during follow-up to start preemptive therapy before overt morphologic relapse.
    DOI:  https://doi.org/10.1038/s41375-024-02335-2
  4. Leukemia. 2024 Jul 18.
    Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.
    Jiachen Wang, Yu Zhang, Lei Li, Liujiao Wang, Shuainan Sun, Bowu Wang, Yanwen Ge, Zhonghui Zhang.
      NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.
    DOI:  https://doi.org/10.1038/s41375-024-02352-1
  5. Am J Hematol. 2024 Jul 17.
    Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?
    Jennifer Marvin-Peek, Jason S Gilbert, Daniel A Pollyea, Courtney D DiNardo.
      The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.
    DOI:  https://doi.org/10.1002/ajh.27434
  6. J Clin Oncol. 2024 Jul 19. JCO2400108
    Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.
    Rathana Kim, Yves Chalandon, Philippe Rousselot, Jean-Michel Cayuela, Françoise Huguet, Marie Balsat, Marie Passet, Patrice Chevallier, Yosr Hicheri, Emmanuel Raffoux, Thibaut Leguay, Sylvain Chantepie, Sébastien Maury, Sandrine Hayette, Françoise Solly, Thorsten Braun, Bernard De Prijck, Victoria Cacheux, Celia Salanoubat, Laure Farnault, Isabelle Guibaud, Mathilde Lamarque, Lauris Gastaud, Emilie Lemasle, Eolia Brissot, Emmanuelle Tavernier, Karine Bilger, Alban Villate, Jean Soulier, Carlos Graux, Véronique Lhéritier, Hervé Dombret, Nicolas Boissel, Emmanuelle Clappier.
      PURPOSE: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor (IG/TR) gene markers.PATIENTS AND METHODS: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT).
    RESULTS: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1-positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 109/L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT.
    CONCLUSION: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.
    DOI:  https://doi.org/10.1200/JCO.24.00108
  7. Leukemia. 2024 Jul 18.
    Clinical and molecular characteristics of extramedullary acute myeloid leukemias.
    Tariq Kewan, Waled S Bahaj, Carmelo Gurnari, Olisaemeka D Ogbue, Sudipto Mukherjee, Anjali Advani, James R Cook, Heesun J Rogers, Hetty E Carraway, Suresh K Balasubramanian, Valeria Visconte, Jaroslaw P Maciejewski.
      
    DOI:  https://doi.org/10.1038/s41375-024-02337-0
  8. Am J Hematol. 2024 Jul 17.
    Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia.
    Sanam Loghavi, Qing Wei, Farhad Ravandi, Andres E Quesada, Mark J Routbort, Shimin Hu, Gokce A Toruner, Sa A Wang, Wei Wang, Roberto N Miranda, Shaoying Li, Jie Xu, Courtney D DiNardo, Naval Daver, Tapan M Kadia, Ghayas C Issa, Hagop M Kantarjian, L Jeffrey Medeiros, Guilin Tang.
      Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (n = 23), KMT2A partial tandem duplication (n = 11), rearrangements involving MECOM (n = 7), NUP98 (n = 2), KMT2A (n = 2), JAK2 (n = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.
    DOI:  https://doi.org/10.1002/ajh.27435
  9. Cell Rep Med. 2024 Jul 16. pii: S2666-3791(24)00359-8. [Epub ahead of print]5(7): 101645
    Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.
    Meiling Chen, Chao Shen, Yi Chen, Zhenhua Chen, Keren Zhou, Yuanzhong Chen, Wei Li, Chengwu Zeng, Ying Qing, Dong Wu, Caiming Xu, Tingting Tang, Yuan Che, Xi Qin, Zhaoxu Xu, Kitty Wang, Keith Leung, Lillian Sau, Xiaolan Deng, Jianda Hu, Yong Wu, Jianjun Chen.
      Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.
    Keywords:  AML; FLT3-ITD; FLT3-mutated; MAPK/mTOR; PLK1; TKI-resistant; combinational therapy; gilteritinib; metformin; synergy
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101645
  10. Eur J Haematol. 2024 Jul 18.
    Real-world effectiveness of first-line azacitidine or decitabine with or without venetoclax in acute myeloid leukemia patients unfit for intensive therapy.
    Fabian Acker, Jörg Chromik, Emily Tiedjen, Sebastian Wolf, Jonas B Vischedyk, Philipp Makowka, Julius C Enßle, Khouloud Kouidri, Martin Sebastian, Björn Steffen, Thomas Oellerich, Hubert Serve, Andreas Neubauer, Jonas A Schäfer, Jörg T Bittenbring.
      BACKGROUND: First-line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results.METHODS: We performed a multicenter retrospective analysis of outcomes with first-line HMA-VEN versus HMA in AML patients unfit for intensive chemotherapy.
    RESULTS: A total of 213 patients were included from three German hospitals (125 HMA-VEN, 88 HMA). Median overall survival in the HMA-VEN cohort was 7.9 months (95% confidence interval [CI], 5.1-14.7) versus 4.9 months (3.1-7.1) with HMA. After 1 year, 42% (95% CI, 33-54) and 19% (12-30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46-0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA-VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29-0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47-0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33-0.84).
    DISCUSSION: These data align with findings from the pivotal VIALE-A trial and support the use of HMA-VEN in patients unfit for intensive therapy.
    Keywords:  AML; azacitidine; decitabine; hypomethylating agent; real‐world data; venetoclax
    DOI:  https://doi.org/10.1111/ejh.14278
  11. Cancer Res. 2024 Jul 18.
    Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.
    Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Bjorn Haupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier.
      Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. Here, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the beta subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the alpha subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells both through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. ATP1B3 is thus a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3560
  12. JCO Oncol Pract. 2024 Jul 16. OP2400027
    Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.
    Fadi G Haddad, Koji Sasaki, Jayastu Senapati, Lianchun Xiao, Grace Park, Tareq Abuasab, Sangeetha Venugopal, Daniel Rivera, Alexandre Bazinet, Rodrick Babakhanlou, Kunhwa Kim, Faustine Ong, Sai Desikan, Naveen Pemmaraju, Sanam Loghavi, Gautam Borthakur, Courtney DiNardo, Hussein A Abbas, Nicholas J Short, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan Kadia.
      PURPOSE: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality.METHODS: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 109/L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS.
    RESULTS: The median age was 65 years (range, 23-86); the median WBC was 146 × 109/L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3, NPM1, and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109/L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS.
    CONCLUSION: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.
    DOI:  https://doi.org/10.1200/OP.24.00027
  13. Adv Exp Med Biol. 2024 ;1459 405-430
    HOXA9 Regulome and Pharmacological Interventions in Leukemia.
    Sajesan Aryal, Rui Lu.
      HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.
    Keywords:  Biomarkers; Epigenetics; Gene regulation; Hematopoiesis; Homeobox A9 (HOXA9); Leukemia; Prognostic implications; Therapeutic strategies; Transcription factors
    DOI:  https://doi.org/10.1007/978-3-031-62731-6_18
  14. Blood Cancer J. 2024 Jul 19. 14(1): 116
    Myeloid neoplasms arising after methotrexate therapy for autoimmune rheumatological diseases do not exhibit poor-risk molecular features.
    Mihir D Wechalekar, Lin-Pierre Zhao, Monika M Kutyna, Lih En Hong, Joule Li, Kevin Hung, Hamish S Scott, Anna Brown, Christopher C Hahn, Karin Kassahn, Dariusz Ladon, David T Yeung, Daniel Thomas, Mrinal Patnaik, Susanna Proudman, Lionel Ades, Mithun V Shah, Chung H Kok, Devendra K Hiwase.
      
    DOI:  https://doi.org/10.1038/s41408-024-01093-9
  15. Br J Haematol. 2024 Jul 14.
    Clinical utility of investigations in triple-negative thrombocytosis: A real-world, multicentre evaluation of UK practice.
    Anna L Godfrey, Nikolaos Sousos, Rebecca Frewin, Mahesh Prahladan, Anna C Green, Andrew McGregor, Alesia Khan, Kate Milne, Faisal Amin, Elena Torre, Emma J Gudgin, Jonathan Lambert, Andrew J Wilson, Daniel Royston, Claire N Harrison, Adam J Mead.
      Diagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple-negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm-definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real-world 'triple-negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP-negative cases and that specific guidelines are needed.
    Keywords:  diagnosis; molecular; myeloproliferative; thrombocytosis; triple‐negative
    DOI:  https://doi.org/10.1111/bjh.19643
  16. Blood. 2024 07 12. pii: blood.2024024342. [Epub ahead of print]
    Hope for Motherhood: Pregnancy After Allogeneic Hematopoietic Cell Transplantation - a National Multicenter Study.
    Katja Sockel, Annika Neu, Maren Goeckenjan, Markus Ditschkowski, Inken Hilgendorf, Nicolaus Kroeger, Francis Ayuketang Ayuk, Friedrich Stölzel, Jan M Middeke, Matthias Eder, Wolfgang Andreas Bethge, Jürgen Finke, Hartmut Bertz, Guido Kobbe, Martin Kaufmann, Uwe Platzbecker, David Beverungen, Christoph Schmid, Malte von Bonin, Katharina Egger-Heidrich, Lisa Heberling, Karolin Trautmann-Grill, Raphael Teipel, Gesine Bug, Johanna Tischer, Alessia Fraccaroli, Matthias Alexander Fante, Daniel Wolff, Thomas Luft, Julia Winkler, Kerstin Schäfer-Eckart, Christof Scheid, Udo Holtick, Stefan Klein, Igor Blau, Andreas Burchert, Gerald Georg Wulf, Justin Hasenkamp, Rainer Schwerdtfeger, Stephan Kaun, Christian Junghanss, Friederike Wortmann, Susann Winter, Helga Neidlinger, Catrin Theuser, Jan Beyersmann, Martin Bornhäuser, Sandra Schmeller, Johannes Schetelig.
      Improved long-term survival rates after allogeneic hematopoietic cell transplantation (alloHCT) make family planning for young adult cancer survivors an important topic. However, treatment-related infertility risk poses challenges. To assess pregnancy and birth rates in a contemporary cohort, we conducted a national multicenter study using data from the German Transplant Registry, focusing on adult women aged 18-40 who underwent alloHCT between 2003 and 2018. Out of 2,654 transplanted women, 50 women experienced 74 pregnancies, occurring at a median of 4.7 years post-transplant. Fifty-seven of these resulted in live births (77%). The annual first birth rate among HCT recipients was 0.45% (95%CI: 0.31 - 0.59%), which is more than six times lower than in the general population. The probability of a live birth 10 years after HCT was 3.4 % (95%CI: 2.3- 4.5%). Factors associated with an increased likelihood of pregnancy were younger age at alloHCT, non-malignant transplant indications, no total-body-irradiation (TBI) or a cumulative dose of <8 Gray, and non-myeloablative/reduced-intensity conditioning. 72% of pregnancies occurred spontaneously, with assisted reproductive technologies (ART) used in the remaining cases. Preterm delivery and low birth weight were more common than in the general population. This study represents the largest dataset reporting pregnancies in a cohort of adult female alloHCT recipients. Our findings underscore a meaningful chance of pregnancy in alloHCT recipients. ART techniques are important and funding should be made available. However, the potential for spontaneous pregnancies should not be underestimated, and patients should be informed of the possibility of unexpected pregnancy despite reduced fertility. Further research is warranted to understand the impact of conditioning decisions on fertility preservation.
    DOI:  https://doi.org/10.1182/blood.2024024342
  17. Blood Adv. 2024 Jul 15. pii: bloodadvances.2024013468. [Epub ahead of print]
    Unrelated donor transplantation with post-transplant cyclophosphamide versus ATG for myelodysplastic neoplasms.
    Yves Chalandon, Diderik-Jan Eikema, Ivan Sergeevich Moiseev, Fabio Ciceri, Linda Koster, Jan Vydra, Jakob R Passweg, Montserrat Rovira, Tulay Ozcelik, Tobias Gedde-Dahl, Nicolaus Kröger, Victoria Potter, Ibrahim Yakoub-Agha, Alessandro Rambaldi, Maija Itälä-Remes, Alina D Tanase, Francesco Onida, Carmelo Gurnari, Christof Scheid, Joanna Drozd-Sokolowska, Kavita Raj, Donal P McLornan, Marie Robin.
      Prospective randomized trials have reported a benefit for anti-thymocyte globulin (ATG)-based graft-versus-host disease (GvHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with unrelated donors (UD). However, the optimal GvHD prophylaxis strategy has been recently challenged by the increasing use of post-transplant cyclophosphamide (PTCY). We report from the EBMT registry the outcomes of 960 patients with myelodysplastic neoplasms (MDS) undergoing allo-HSCT from UD with PTCY or ATG as GvHD prophylaxis. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%, p<0.001). With a median follow-up of 4.4 years (95% confidence interval [CI] 4.2 - 4.8), 5-year OS was 58% (95% CI 50-65) with PTCY and 49% (95% CI 46-53%) in the ATG group, p=0.07. 5-year PFS was higher for PTCY with 53% (95% CI 45-60) vs 44% (95% CI 40-48) for ATG, p=0.043. Grade II-IV aGvHD incidence was lower using PTCY (23% [95% CI 17-29%] vs 30% [95% CI 27-33%]), p=0.044 while there was no difference in incidence of cGvHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY, with a HR for ATG of 1.32 (1 - 1.74), p=0.05, and a better PFS for PTCY with a HR for ATG of 1.33 (1.03 - 1.73), p=0.03. This study suggests that GvHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013468
  18. Cardiooncology. 2024 Jul 15. 10(1): 42
    Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score.
    Fiona Fernando, Maria Sol Andres, Simone Claudiani, Nazanin Zounemat Kermani, Giulia Ceccarelli, Andrew J Innes, Afzal Khan, Stuart D Rosen, Jane F Apperley, Alexander R Lyon, Dragana Milojkovic.
      BACKGROUND: The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, showed higher rates of major molecular response than imatinib, however associated with higher cardiovascular (CV) toxicity. We sought to describe the CV events associated with nilotinib in a real-world population and assess the predictive value of the HFA-ICOS risk score.METHODS: The HFA-ICOS baseline risk was calculated for patients with CML treated with nilotinib beween 2006 and 2021. The primary end point was the incidence of all CV events. The secondary end point was the incidence of ischaemic events. Survival analysis evaluated the risk (hazard ratio [HR]) of events stratified by baseline risk category, whilst on nilotinib therapy.
    RESULTS: Two hundred and twenty-nine eligible patients were included. The incidence of CV events was 20.9% (95% CI: 15.7-26.2%) following a median duration of treatment of 34.4 months. The secondary end point occurred in 12.7% (95% CI: 8.4-16.9%) of the population. Patients with higher HFA-ICOS baseline score had higher rates of CV events (low: 11.2%, medium: 28.2% [HR: 2.51, 95% CI: 1.17-5.66], high/very high: 32.4% [HR: 3.57, 95% CI: 1.77-7.20]) and ischaemic events (low: 5.20%, medium: 17.9% [HR: 2.19, 95% CI: 0.97-4.96], high/very high: 21.6% [HR: 3.9, 95% CI: 1.91-7.89]). In patients who did not have a CV event, the median total dose at last follow up or cessation of nilotinib therapy was lower when compared to the total daily median dose of nilotinib in patients who had a CV event (450 mg vs. 600 mg, p = 0.0074).
    CONCLUSIONS: The HFA-ICOS risk stratification tool is an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk catergories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients.
    Keywords:  CV toxicity; Chronic myeloid leukaemia; Nilotinib; Risk stratification; TKI
    DOI:  https://doi.org/10.1186/s40959-024-00245-x
  19. J Biol Chem. 2024 Jul 11. pii: S0021-9258(24)02067-2. [Epub ahead of print] 107566
    MLL-AF9 regulates transcriptional initiation in mixed lineage leukemic cells.
    Zimei Yang, Ge Zhang, Ruoyu Zhao, Tian Tian, Junhong Zhi, Gang Wei, Robert G Roeder, Lili Jing, Ming Yu.
      MLL-fusion proteins (MLL-FPs) are believed to maintain gene activation and induce mixed lineage leukemia (MLL) through aberrantly stimulating transcriptional elongation, but the underlying mechanisms are incompletely understood. Here we show that both MLL1 and AF9, one of the major fusion partners of MLL1, mainly occupy promoters and distal intergenic regions, exhibiting chromatin occupancy patterns resembling that of RNA polymerase II (Pol II) in HEL, a human cell line without MLL1 arrangement (MLLr). MLL1 and AF9 only co-regulate over a dozen genes despite of their co-occupancy on thousands of genes. They do not interact with each other, and their chromatin occupancy is also independent of each other. Moreover, AF9 deficiency in HEL cells decreases global TBP occupancy while decreases CDK9 occupancy on a small number of genes, suggesting an accessory role of AF9 in CDK9 recruitment and a possible major role in transcriptional initiation via initiation factor recruitment. Importantly, MLL1 and MLL-AF9 occupy promoters and distal intergenic regions, exhibiting identical chromatin occupancy patterns in MLL cells, and MLL-AF9 deficiency decreased occupancy of TBP and TFIIE on major target genes of MLL-AF9 in iMA9, a murine acute myeloid leukemia (AML) cell line inducibly expressing MLL-AF9, suggesting that it can also regulate initiation. These results suggest that there is no difference between MLL1 and MLL-AF9 with respect to location and size of occupancy sites, contrary to what people have believed, and that MLL-AF9 may also regulate transcriptional initiation in addition to widely-believed elongation.
    Keywords:  AF9; MLL-AF9; MLL1; initiation; mixed lineage leukemia; super elongation complex
    DOI:  https://doi.org/10.1016/j.jbc.2024.107566
  20. Blood. 2024 Jul 19. pii: blood.2023023660. [Epub ahead of print]
    Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation.
    Leslie S Kean, Linda J Burns, Tzuyung D Kou, Roxanne Kapikian, Karissa Lozenski, Amelia Langston, John T Horan, Benjamin Watkins, Muna Qayed, Brandi Bratrude, Kayla Betz, Xiao-Ying Tang, Mei-Jie Zhang, Sean E Connolly, Martin Sander Polinsky, Brian J Gavin, Andres Gomez-Caminero, Marcelo C Pasquini.
      Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first FDA-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). We investigated its impact in URD-HCT patients using Center for International Blood and Marrow Transplant Research data for 7/8-human leukocyte antigen (HLA)-mismatched (MMUD) or 8/8-HLA-matched (MUD) URD-HCT recipients between 2011-2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept+CNI/MTX vs CNI/MTX, CNI/MTX+antithymocyte globulin (ATG), and post-transplant cyclophosphamide-based prophylaxis (PT-Cy); other outcomes included aGVHD, chronic GVHD, non-relapse mortality, and relapse. For 7/8-MMUDs, day-180 OS (primary endpoint supporting FDA approval) was significantly higher for abatacept+CNI/MTX vs CNI/MTX (98%vs75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (83%vs55%; p=0.0036), CNI/MTX+ATG (83%vs46%; p=0.0005) and similar to PT-Cy (80%vs68%; p=0.2325). Two-year RFS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (74%vs49%; p=0.0098) and CNI/MTX+ATG (77%vs35%; p=0.0002), and similar vs PT-Cy (72%vs56%; p=0.1058). For 8/8-MUDs, 2-year OS was similar with abatacept+CNI/MTX vs CNI/MTX (70%vs62%; p=0.2569), CNI/MTX+ATG (75%vs64%; p=0.1048), and PT-Cy (74%vs69%; p=0.5543). Two-year RFS for abatacept+CNI/MTX was numerically higher vs CNI/MTX (63%vs52%; p=0.1497) with an improved hazard ratio (HR: 0.46 [0.25-0.86]), and vs CNI/MTX+ATG (66%vs55%; p=0.1193; HR: 0.39 [0.21-0.73]). Two-year RFS was similar vs PT-Cy (68%vs57%; p=0.2356; HR: 0.54 [0.26-1.11]). For both 7/8-MMUD and 8/8-MUD recipients, abatacept+CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX+ATG; outcomes were similar to PT-Cy-based regimens. Abatacept+CNI/MTX has potential to facilitate unrelated donor pool expansion for HCT.
    DOI:  https://doi.org/10.1182/blood.2023023660
  21. Leukemia. 2024 Jul 18.
    Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis.
    Daniele Capitanio, Francesca R Calledda, Vittorio Abbonante, Daniele Cattaneo, Manuela Moriggi, Bartalucci Niccolò, Cristina Bucelli, Delfina Tosi, Umberto Gianelli, Alessandro Maria Vannucchi, Alessandra Iurlo, Cecilia Gelfi, Alessandra Balduini, Alessandro Malara.
      Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.
    DOI:  https://doi.org/10.1038/s41375-024-02354-z
  22. J Clin Oncol. 2024 Jul 17. JCO2400184
    Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors.
    Brian C Shaffer, Mahasweta Gooptu, Todd E DeFor, Martin Maiers, Javier Bolaños-Meade, Ramzi Abboud, Adrienne D Briggs, Farhad Khimani, Dipenkumar Modi, Richard Newcomb, Elizabeth J Shpall, Caitrin Bupp, Stephen R Spellman, Heather E Stefanski, Bronwen E Shaw, Jeffery J Auletta, Steven M Devine, Antonio M Jimenez Jimenez, Monzr M Al Malki.
      PURPOSE: Access to allogeneic hematopoietic cell transplantation (HCT) remains limited among persons of non-European ancestry if human leukocyte antigen (HLA) matching is required. We evaluated whether post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis improved HCT outcomes with HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HCT when compared with calcineurin inhibitor (CNI)-based prophylaxis.METHODS: Three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were compared between adult recipients undergoing initial MUD or single HLA locus MMUD HCT with either PTCy- or CNI-based prophylaxis who were reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021.
    RESULTS: Included were 10,025 HCT recipients (7,272 recipients of MUD with CNI, 1,681 MUD with PTCy, 613 MMUD with CNI, and 459 MMUD with PTCy) who underwent HCT for acute leukemia (70.9%) or myelodysplastic syndromes (29.2%). Median patient age was 60.7 years (range, 18.0-82.7) and median follow-up was 36.6 (range, 3.0-77.8) months. When compared with MUD HCT with PTCy, MMUD HCT with PTCy had similar OS (hazard ratio [HR], 0.96 [95% CI, 0.823 to 1.11]; P = .60) and GRFS (HR, 0.90 [0.79 to 1.02]; P = .1). When compared with MUD HCT with CNI, OS was improved after MUD HCT with PTCy (HR, 0.88 [0.80 to 0.96]; P = .004) and GRFS was improved with PTCy after either MUD (HR, 0.61 [0.57 to 0.66]; P < .0001) or MMUD (HR, 0.68 [0.60 to 0.76]; P < .0001) HCT. Benefit from PTCy was independent of patient ancestry. Global registry level analysis demonstrated that inclusion of MMUD increased donor availability regardless of recipient ancestry.
    CONCLUSION: Use of PTCy results in comparable OS and GRFS using either MUD or MMUD HCT, expanding access to HCT for patients from all racial and ethnic ancestry groups.
    DOI:  https://doi.org/10.1200/JCO.24.00184
  23. J Clin Oncol. 2024 Jul 19. JCO2400272
    Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.
    Hagop Kantarjian, Nicholas J Short, Fadi G Haddad, Nitin Jain, Xuelin Huang, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Tapan M Kadia, Naval Daver, Kelly Chien, Yesid Alvarado, Guillermo Garcia-Manero, Ghayas C Issa, Rebecca Garris, Cedric Nasnas, Lewis Nasr, Farhad Ravandi, Elias Jabbour.
      Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.
    DOI:  https://doi.org/10.1200/JCO.24.00272
  24. Exp Hematol. 2024 Jul 13. pii: S0301-472X(24)00140-1. [Epub ahead of print] 104281
    Mobilization dynamics of bone marrow hematopoietic stem cells during hematopoietic regeneration.
    Alban Johansson, Ahad Khalilnezhad, Hitoshi Takizawa, Hidenobu Mizuno, Toshio Suda, Terumasa Umemoto.
      Under stress hematopoiesis, previous studies have suggested the migration of hematopoietic stem cells (HSCs) from bone marrow (BM) to extramedullary sites such as spleen. However, there is little direct evidence of HSC migration from BM to spleen. Here, we induced myeloablation via 5-fluorouracil (5-FU) and showed the direct evidence of HSC migration from BM to spleen during hematopoietic regeneration via a photoconvertible fluorophore. Moreover, during steady-state, HSCs preferentially migrated to BM rather than spleen, but during hematopoietic regeneration HSCs preferred to spleen as a migration site equivalently or greater. Furthermore, in the early phase, HSCs egressed from BM through the attenuated HSC retention. However, HSCs in the late phase gained significantly enhanced cell-autonomous motility, which was independent of chemotaxis. Collectively, HSC mobilization from BM prior to the migration to spleen was dynamically changed from passive to active events during hematopoietic regeneration.
    Keywords:  Bone marrow regeneration; Cell migration; Extramedullary hematopoiesis; Hematopoietic stem cell
    DOI:  https://doi.org/10.1016/j.exphem.2024.104281
  25. Clin Exp Med. 2024 Jul 13. 24(1): 155
    Novel Vpx virus-like particles to improve cytarabine treatment response against acute myeloid leukemia.
    Ramya Nair, Alejandro Salinas-Illarena, Monika Sponheimer, Inès Wullkopf, Yannick Schreiber, João Vasco Côrte-Real, Augusto Del Pozo Ben, Helena Marterer, Dominique Thomas, Gerd Geisslinger, Jindrich Cinatl, Marion Subklewe, Hanna-Mari Baldauf.
      Knowledge of the molecular pathogenesis of acute myeloid leukemia has advanced in recent years. Despite novel treatment options, acute myeloid leukemia remains a survival challenge for elderly patients. We have recently shown that the triphosphohydrolase SAMHD1 is one of the factors determining resistance to Ara-C treatment. Here, we designed and tested novel and simpler virus-like particles incorporating the lentiviral protein Vpx to efficiently and transiently degrade SAMHD1 and increase the efficacy of Ara-C treatment. The addition of minute amounts of lentiviral Rev protein during production enhanced the generation of virus-like particles. In addition, we found that our 2nd generation of virus-like particles efficiently targeted and degraded SAMHD1 in AML cell lines with high levels of SAMHD1, thereby increasing Ara-CTP levels and response to Ara-C treatment. Primary AML blasts were generally less responsive to VLP treatment. In summary, we have been able to generate novel and simpler virus-like particles that can efficiently deliver Vpx to target cells.
    Keywords:  AML; Cytarabine; Resistance; SAMHD1; VLP; Vpx
    DOI:  https://doi.org/10.1007/s10238-024-01425-w
  26. Leukemia. 2024 Jul 16.
    FBXL6 is a vulnerability in AML and unmasks proteolytic cleavage as a major experimental pitfall in myeloid cells.
    Anna Sperk, Antje Gabriel, Daniela Koch, Abirami Augsburger, Victoria Sanchez, David Brockelt, Rupert Öllinger, Thomas Engleitner, Piero Giansanti, Romina Ludwig, Priska Auf der Maur, Wencke Walter, Torsten Haferlach, Irmela Jeremias, Roland Rad, Barbara Steigenberger, Bernhard Kuster, Ruth Eichner, Florian Bassermann.
      
    DOI:  https://doi.org/10.1038/s41375-024-02345-0
  27. Blood Cancer J. 2024 Jul 16. 14(1): 114
    Using Mendelian Randomisation to search for modifiable risk factors influencing the development of clonal haematopoiesis.
    Jessica M Hislop, Molly Went, Charlie Mills, Amit Sud, Philip J Law, Richard S Houlston.
      
    DOI:  https://doi.org/10.1038/s41408-024-01101-y
  28. Leukemia. 2024 Jul 17.
    Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms.
    Carlo Zaninetti, Leonard Vater, Lars Kaderali, Carl C Crodel, Tina M Schnöder, Jessica Fuhrmann, Leonard Swensson, Jan Wesche, Carmen Freyer, Andreas Greinacher, Florian H Heidel.
      
    DOI:  https://doi.org/10.1038/s41375-024-02346-z
  29. Blood Adv. 2024 Jul 15. pii: bloodadvances.2024013677. [Epub ahead of print]
    Interplay between donor age and HLA-DP matching in 10/10 HLA-matched unrelated donor HCT.
    Rohtesh S Mehta, Effie W Petersdorf, Tao Wang, Stephen R Spellman, Stephanie J Lee.
      In 10/10 HLA-matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) with calcineurin-inhibitor (CNI)-based prophylaxis, T-cell epitope DP-matched and permissive mismatched donors are associated with similar overall survival (OS) while donors with non-permissive mismatches should be avoided. Younger unrelated donors are also favored over older donors. We explored outcomes associated with different combinations of DP-matching and donor age (dichotomized at 35 years) to further guide donor selection. Using a Center for International Blood and Marrow Transplant Research dataset, we categorized 10,783 patients into six groups: DP-matched/younger donor (n=1591), DP-matched/older donor (n=526), permissive-mismatched/younger donor (n=3845), permissive-mismatched/older donor (n=1184), non-permissive mismatched/younger donor (n=2659), non-permissive mismatched/older donor (n=978). We noted that younger donor age, rather than DP-matching, was associated with better OS. Younger donors with permissive mismatches were associated with improved OS compared to older matched donors. Furthermore, younger donors with non-permissive mismatches were associated with improved OS compared to older donors with permissive mismatches. Our study adds further information about the association of DP-matching and donor age with HCT outcomes. Donor age should be prioritized over DP-matching in patients undergoing 10/10 HLA-MUD with CNI prophylaxis. Among those with younger donors, permissive-mismatched or DP-matched donors are preferred over non-permissive mismatched donors.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013677
  30. Nature. 2024 Jul 17.
    In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.
    Peter F Renz, Umesh Ghoshdastider, Simona Baghai Sain, Fabiola Valdivia-Francia, Ameya Khandekar, Mark Ormiston, Martino Bernasconi, Clara Duré, Jonas A Kretz, Minkyoung Lee, Katie Hyams, Merima Forny, Marcel Pohly, Xenia Ficht, Stephanie J Ellis, Andreas E Moor, Ataman Sendoel.
      The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-07663-y
  31. Nature. 2024 Jul 17.
    Clonal inactivation of TERT impairs stem cell competition.
    Kazuteru Hasegawa, Yang Zhao, Alina Garbuzov, M Ryan Corces, Patrick Neuhöfer, Victoria M Gillespie, Peggie Cheung, Julia A Belk, Yung-Hsin Huang, Yuning Wei, Lu Chen, Howard Y Chang, Steven E Artandi.
      Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres-nucleoprotein caps that protect chromosome ends1. Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner2-8, but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function. In many tissues, homeostasis is shaped by stem cell competition, a process in which stem cells compete on the basis of inherent fitness. Here we show that conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation. Using lineage tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin. This role for TERT in competitive clone formation occurs independently of both its reverse transcriptase activity and the canonical telomerase complex. Inactivation of TERT causes reduced activity of the MYC oncogene, and transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation. Together, these data reveal a catalytic-activity-independent requirement for TERT in enhancing stem cell competition, uncover a genetic connection between TERT and MYC and suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and ageing.
    DOI:  https://doi.org/10.1038/s41586-024-07700-w
  32. Blood. 2024 Jul 15. pii: blood.2023022735. [Epub ahead of print]
    Chronic graft-versus-host disease: Unresolved complication or ancient history?
    Joseph A Pidala, Theodore A Gooley, Leo Luznik, Bruce R Blazar.
      Chronic graft-vs.-host disease (GVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive (IS) therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of chronic GVHD biology, NIH Consensus meetings have refined rigorous approaches to diagnosis, staging and response criteria, major interventional trials have established standard benchmarks for treatment outcome, and three agents to date have been FDA-approved for treating steroid-refractory chronic GVHD. Promising results from several recent trials have led some but not others to conclude that the risk of developing chronic GVHD is sufficiently low to by-and-large be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary GVHD prophylaxis regimens and discuss the state-of-the-science and associated controversies in spectrum of conclusions reached as to the risk of chronic GVHD. With these data, the current chronic GVHD incidence can be most precisely determined, and the present and future burden of chronic GVHD-affected patients be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches, optimize established chronic GVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.
    DOI:  https://doi.org/10.1182/blood.2023022735
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