bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–12–26
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD+ Acute Myeloid Leukemia.
  2. Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients.
  3. Mouse Models of Frequently Mutated Genes in Acute Myeloid Leukemia.
  4. Azacitidine and Durvalumab in First-line Treatment of Elderly Patients With Acute Myeloid Leukemia.
  5. Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia.
  6. Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia.
  7. The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed.
  8. Venetoclax and hypomethylating agents yield high response rates and favourable transplant outcomes in patients with newly diagnosed acute myeloid leukaemia.
  9. KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility.
  10. Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome.
  11. Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.
  12. WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia.
  13. Humanized 3D scaffold xenotransplantation models for Myelodysplastic Syndromes.
  14. SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.
  15. Prognostic scoring systems and risk stratification in myelodysplastic syndrome: focus on integration of molecular profile.
  16. MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.
  17. PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.
  18. Valine tRNA levels and availability regulate complex I assembly in leukaemia.
  19. Identification of RIOK2 as a master regulator of human blood cell development.
  20. Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
  21. Clonal hematopoiesis associates with improved survival in metastatic colorectal cancer patients from the FIRE-3 trial.
  22. Transcriptional differences between JAK2-V617F and wild-type bone marrow cells in myeloproliferative neoplasm patients.
  23. Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment.
  1. Cancers (Basel). 2021 Dec 08. pii: 6181. [Epub ahead of print]13(24):
    Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD+ Acute Myeloid Leukemia.
    Javier Bregante, Anna Schönbichler, Daniel Pölöske, Lina Degenfeld-Schonburg, Garazi Monzó Contreras, Emir Hadzijusufovic, Elvin D de Araujo, Peter Valent, Richard Moriggl, Anna Orlova.
      Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring FLT3-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, FLT3-ITD+ AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against FLT3-ITD+ AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in FLT3-ITD+ AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in FLT3-ITD+ AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting FLT3-ITD+ AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in FLT3-ITD+ AML remains to be determined in clinical trials.
    Keywords:  FMS-like tyrosine kinase 3; WS6; acute myeloid leukemia; cabozantinib; ispinesib; ponatinib; targeted therapy; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3390/cancers13246181
  2. Cancers (Basel). 2021 Dec 17. pii: 6353. [Epub ahead of print]13(24):
    Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients.
    Quentin Fovez, William Laine, Laure Goursaud, Celine Berthon, Nicolas Germain, Claire Degand, Jean-Emmanuel Sarry, Bruno Quesnel, Philippe Marchetti, Jerome Kluza.
      Resistant acute myeloid leukemia (AML) exhibits mitochondrial energy metabolism changes compared to newly diagnosed AML. This phenotype is often observed by evaluating the mitochondrial oxygen consumption of blasts, but most of the oximetry protocols were established from leukemia cell lines without validation on primary leukemia cells. Moreover, the cultures and storage conditions of blasts freshly extracted from patient blood or bone marrow cause stress, which must be evaluated before determining oxidative phosphorylation (OXPHOS). Herein, we evaluated different conditions to measure the oxygen consumption of blasts using extracellular flow analyzers. We first determined the minimum number of blasts required to measure OXPHOS. Next, we compared the OXPHOS of blasts cultured for 3 h and 18 h after collection and found that to maintain metabolic organization for 18 h, cytokine supplementation is necessary. Cytokines are also needed when measuring OXPHOS in cryopreserved, thawed and recultured blasts. Next, the concentrations of respiratory chain inhibitors and uncoupler FCCP were established. We found that the FCCP concentration required to reach the maximal respiration of blasts varied depending on the patient sample analyzed. These protocols provided can be used in future clinical studies to evaluate OXPHOS as a biomarker and assess the efficacy of treatments targeting mitochondria.
    Keywords:  OCR; XFe24 Seahorse; XFe96 Seahorse; energy metabolism; functional biomarker; leukemia; resistance; uncoupling respiration
    DOI:  https://doi.org/10.3390/cancers13246353
  3. Cancers (Basel). 2021 Dec 08. pii: 6192. [Epub ahead of print]13(24):
    Mouse Models of Frequently Mutated Genes in Acute Myeloid Leukemia.
    Sagarajit Mohanty, Michael Heuser.
      Acute myeloid leukemia is a clinically and biologically heterogeneous blood cancer with variable prognosis and response to conventional therapies. Comprehensive sequencing enabled the discovery of recurrent mutations and chromosomal aberrations in AML. Mouse models are essential to study the biological function of these genes and to identify relevant drug targets. This comprehensive review describes the evidence currently available from mouse models for the leukemogenic function of mutations in seven functional gene groups: cell signaling genes, epigenetic modifier genes, nucleophosmin 1 (NPM1), transcription factors, tumor suppressors, spliceosome genes, and cohesin complex genes. Additionally, we provide a synergy map of frequently cooperating mutations in AML development and correlate prognosis of these mutations with leukemogenicity in mouse models to better understand the co-dependence of mutations in AML.
    Keywords:  AML; leukemia; mouse models; mutations; synergy; transgenic mice
    DOI:  https://doi.org/10.3390/cancers13246192
  4. Blood Adv. 2021 Dec 21. pii: bloodadvances.2021006138. [Epub ahead of print]
    Azacitidine and Durvalumab in First-line Treatment of Elderly Patients With Acute Myeloid Leukemia.
    Amer M Zeidan, Isaac Wayne Boss, C L Beach, Wilbert B Copeland, Ethan Greene Thompson, Brian A Fox, Vanessa E Hasle, Andrzej Hellmann, David Taussig, Mar Tormo, Maria Teresa Voso, Jamie Cavenagh, Tim O'Connor, Aessandro Previtali, Shelonitda Rose, Lewis R Silverman.
      Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1-7 with (Arm A, n= 64) or without (Arm B, n=65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery [CRi]) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (A, 13.0 months; B, 14.4 months) and duration of response (A, 24.6 weeks; B, 51.7 weeks; P=0.0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (A, 42.2%; B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible, but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006138
  5. Cancers (Basel). 2021 Dec 13. pii: 6258. [Epub ahead of print]13(24):
    Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia.
    Luciana Melo Garcia, Frédéric Barabé.
      CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called "don't eat me signal" because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.
    Keywords:  CD47; acute myeloid leukemia; phagocytosis
    DOI:  https://doi.org/10.3390/cancers13246258
  6. Cancers (Basel). 2021 Dec 07. pii: 6157. [Epub ahead of print]13(24):
    Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia.
    Marius Maucher, Micha Srour, Sophia Danhof, Hermann Einsele, Michael Hudecek, Ibrahim Yakoub-Agha.
      Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an 'ideal' target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them.
    Keywords:  AML; CAR-T-cell; adoptive cell therapy; gene therapy; hematology
    DOI:  https://doi.org/10.3390/cancers13246157
  7. Cancer Med. 2021 Dec 24.
    The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed.
    Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A S Koster, Bronno van der Holt, Markus G Manz, Dimitri A Breems, Bjorn T Gjertsen, Jacqueline Cloos, Peter J M Valk, Jakob Passweg, Thomas Pabst, Gert J Ossenkoppele, Bob Löwenberg, Jan J Cornelissen, Liesbeth C de Wreede.
      Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.
    Keywords:  AML; HSCT; RCT; clofarabine; current leukemia-free survival; multi-state model
    DOI:  https://doi.org/10.1002/cam4.4392
  8. Br J Haematol. 2021 Dec 21.
    Venetoclax and hypomethylating agents yield high response rates and favourable transplant outcomes in patients with newly diagnosed acute myeloid leukaemia.
    Amandeep Salhotra, Ni-Chun Tsai, Jianying Zhang, Dat Ngo, Ahmed Aribi, Karamjeet Sandhu, Brian Ball, Monzr Al-Malki, Haris Ali, Paul Koller, Andrew Artz, Stephen Forman, Ryotaro Nakamura, Anthony Stein, Guido Marcucci, Ibrahim Aldoss, Vinod Pullarkat.
      
    Keywords:  HMA+Ven; acute myeloid leukaemia (AML)
    DOI:  https://doi.org/10.1111/bjh.17996
  9. FASEB Bioadv. 2021 Dec;3(12): 1020-1033
    KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility.
    Takeshi Ueda, Akinori Kanai, Akiyoshi Komuro, Hisayuki Amano, Kazushige Ota, Masahiko Honda, Masahito Kawazu, Hitoshi Okada.
      Epigenetic alterations of chromatin structure affect chromatin accessibility and collaborate with genetic alterations in the development of cancer. Lysine demethylase 4B (KDM4B) has been identified as a JmjC domain-containing epigenetic modifier that possesses histone demethylase activity. Although recent studies have demonstrated that KDM4B positively regulates the pathogenesis of multiple types of solid tumors, the tissue specificity and context dependency have not been fully elucidated. In this study, we investigated gene expression profiles established from clinical samples and found that KDM4B is elevated specifically in acute myeloid leukemia (AML) associated with chromosomal translocation 8;21 [t(8;21)], which results in a fusion of the AML1 and the eight-twenty-one (ETO) genes to generate a leukemia oncogene, AML1-ETO fusion transcription factor. Short hairpin RNA-mediated KDM4B silencing significantly reduced cell proliferation in t(8;21)-positive AML cell lines. Meanwhile, KDM4B silencing suppressed the expression of AML1-ETO-inducible genes, and consistently perturbed chromatin accessibility of AML1-ETO-binding sites involving altered active enhancer marks and functional cis-regulatory elements. Notably, transduction of murine KDM4B orthologue mutants followed by KDM4B silencing demonstrated a requirement of methylated-histone binding modules for a proliferative surge. To address the role of KDM4B in leukemia development, we further generated and analyzed Kdm4b conditional knockout mice. As a result, Kdm4b deficiency attenuated clonogenic potential mediated by AML1-ETO and delayed leukemia progression in vivo. Thus, our results highlight a tumor-promoting role of KDM4B in AML associated with t(8;21).
    Keywords:  acute myeloid leukemia; chromatin accessibility; gene expression analysis; gene targeting
    DOI:  https://doi.org/10.1096/fba.2021-00030
  10. Blood Adv. 2021 Dec 21. pii: bloodadvances.2021005240. [Epub ahead of print]
    Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome.
    Aaron T Gerds, Bart L Scott, Peter L Greenberg, Tara L Lin, Daniel A Pollyea, Amit K Verma, Monique Dail, Yuning Feng, Cherie Green, Connie Ma, Bruno C Medeiros, Mark Yan, Kasra Yousefi, William B Donnellan.
      We present here primary results from the phase Ib GO29754 study (NCT02508870) evaluating the safety and tolerability of atezolizumab, a PD-L1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naïve myelodysplastic syndrome (MDS). R/R MDS patients received atezolizumab for 12 months (Cohort A), or atezolizumab plus azacitidine for six cycles followed by atezolizumab as maintenance for eight cycles (Cohort B). HMA-naïve MDS patients received atezolizumab plus azacitidine until loss of clinical benefit (Cohort C). Safety, activity, and exploratory endpoints were investigated. Forty-six patients were enrolled and received treatment (11 in Cohort A, 14 in Cohort B, 21 in Cohort C). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In Cohort A, seven patients (63.6%) died, and no patients responded. In Cohort B, eight patients (57.1%) discontinued azacitidine, 11 patients (78.6%) died, and two patients (14.3%) responded. In Cohort C, all 21 patients discontinued azacitidine, 13 patients died (61.9%), and 13 patients (61.9%) responded. The study was terminated by the sponsor prior to completing recruitment due to the unexpected high early death rate in Cohort C (6/13 deaths [46.2%] were due to AEs and occurred within the first four treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naïve MDS.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005240
  11. Leuk Lymphoma. 2021 Dec 19. 1-5
    Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.
    Gail J Roboz, Karen Yee, Amit Verma, Gautam Borthakur, Adolfo de la Fuente Burguera, Guillermo Sanz, Helai P Mohammad, Ryan G Kruger, Natalie O Karpinich, Geraldine Ferron-Brady, Andre Acusta, Heather Del Buono, Therese Collingwood, Marc Ballas, Arindam Dhar, Andrew H Wei.
      
    DOI:  https://doi.org/10.1080/10428194.2021.2012667
  12. Cell Death Dis. 2021 Dec 20. 13(1): 18
    WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia.
    Yunqi Zhu, Xiangmin Tong, Ying Wang, Xiaoya Lu.
      Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.
    DOI:  https://doi.org/10.1038/s41419-021-04467-0
  13. Exp Hematol. 2021 Dec 21. pii: S0301-472X(21)00854-7. [Epub ahead of print]
    Humanized 3D scaffold xenotransplantation models for Myelodysplastic Syndromes.
    Eva Altrock, Carla Sens-Albert, Johann-Christoph Jann, Johanna Flach, Vladimir Riabov, Nanni Schmitt, Qingyu Xu, Arwin Mehralivand, Anna Hecht, Laurenz Steiner, Alexander Streuer, Verena Nowak, Julia Obländer, Nadine Weimer, Iris Palme, Ahmed Jawhar, Cleo-Aron Weis, Vanessa Weyer, Florian Nolte, Mohamad Jawhar, Georgia Metzgeroth, Alexander Marx, Christoph Groden, Wolf-Karsten Hofmann, Daniel Nowak.
      Patient-derived xenograft (PDX) models have emerged as versatile pre-clinical platforms for investigation of functional pathomechanisms in Myelodysplastic Syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized 3D scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been shown to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of 4 different 3D ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM) and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM) derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem- and progenitor cells (HSPCs). Our study included n=13 primary MDS patient samples transplanted in parallel according to these 5 different conditions. Engraftment of MDS samples was assessed by flow cytometry, immunohistological staining and molecular validation. We could show that 3D ossicle based methods achieved higher relative rates of engraftment and enabled long-term retrievability of patient-derived MSCs from implanted ossicles. In summary, HSPCs and MSCs derived from MDS BM, which did not significantly engraft in NSG mice after intrafemoral injection, were able to colonize humanized scaffold models. Therefore, these models are promising new xenotransplantation techniques for addressing pre-clinical and functional questions of the interaction between hematopoiesis and the BM niche in MDS.
    DOI:  https://doi.org/10.1016/j.exphem.2021.12.395
  14. Proc Natl Acad Sci U S A. 2022 Jan 04. pii: e2111703119. [Epub ahead of print]119(1):
    SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.
    Yen K Lieu, Zhaoqi Liu, Abdullah M Ali, Xin Wei, Alex Penson, Jian Zhang, Xiuli An, Raul Rabadan, Azra Raza, James L Manley, Siddhartha Mukherjee.
      SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.
    Keywords:  GATA1; cancer; erythropoiesis; p38 MAPK; spliceosome
    DOI:  https://doi.org/10.1073/pnas.2111703119
  15. Leuk Lymphoma. 2021 Dec 21. 1-11
    Prognostic scoring systems and risk stratification in myelodysplastic syndrome: focus on integration of molecular profile.
    Somedeb Ball, Rami S Komrokji, David A Sallman.
      Myelodysplastic syndromes (MDS) form a clinically and molecularly heterogeneous disease group. Precise risk stratification remains crucial for choosing optimal management strategies. Several conventional prognostic scoring systems have been developed and validated in the MDS population. These risk models divide patients into prognostic subgroups based on clinical and cytogenetic characteristics. Lack of dynamicity, variable risk estimate across models, and heterogeneity within intermediate-risk group are the limitations of traditional models like IPSS-R, with questionable relevance of these scoring systems in treated MDS patients. Recent progress in next-generation sequencing techniques has improved understanding of the distribution and prognostic importance of recurrent genetic mutations in MDS. Early studies have suggested that incorporating mutations in risk stratification could supplement IPSS-R in further refining the model's performance in predicting overall survival and risk of transformation to acute myeloid leukemia and should translate into a molecularly driven prognostication approach in the near future.
    Keywords:  IPSS-R; SF3B1; TP53; artificial intelligence; molecular IPSS; overall survival
    DOI:  https://doi.org/10.1080/10428194.2021.2018579
  16. Blood Adv. 2021 Dec 21. pii: bloodadvances.2021006043. [Epub ahead of print]
    MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.
    John Mascarenhas, Francesco Passamonti, Kate Burbury, Tarec C El-Galaly, Aaron T Gerds, Vikas Gupta, Brian Higgins, Kathrin Wonde, Candice Jamois, Bruno Kovic, Ling-Yuh Huw, Sudhakar Katakam, Margherita Maffioli, Ruben A Mesa, Jeanne M Palmer, Marta Bellini, David M Ross, Alessandro Maria Vannucchi, Abdulraheem Yacoub.
      Idasanutlin, an MDM2 antagonist, showed clinical activity and rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label, phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily, days 1-5 of each 28-day cycle. The primary endpoint was composite response (hematocrit control and spleen volume reduction >35%) in patients with splenomegaly, and hematocrit control in patients without splenomegaly at week 32. Key secondary endpoints included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n=27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n=13), 9 (69%) attained any spleen volume reduction and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (n=6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥3 nausea and vomiting experienced in 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. Registration: NCT03287245.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006043
  17. Cancers (Basel). 2021 Dec 20. pii: 6385. [Epub ahead of print]13(24):
    PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.
    Clifford M Csizmar, Antoine N Saliba, Elizabeth M Swisher, Scott H Kaufmann.
      Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.
    Keywords:  DNA damage repair; PARP inhibitors; acute myeloid leukemia; base excision repair; myelodysplastic syndrome; myeloid neoplasms; non-homologous end-joining; secondary malignancies; synthetic lethality
    DOI:  https://doi.org/10.3390/cancers13246385
  18. Nature. 2021 Dec 22.
    Valine tRNA levels and availability regulate complex I assembly in leukaemia.
    Palaniraja Thandapani, Andreas Kloetgen, Matthew T Witkowski, Christina Glytsou, Anna K Lee, Eric Wang, Jingjing Wang, Sarah E LeBoeuf, Kleopatra Avrampou, Thales Papagiannakopoulos, Aristotelis Tsirigos, Iannis Aifantis.
      Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR-Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Mechanistically, valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I, leading to defective assembly of complex I and impaired oxidative phosphorylation. Finally, a genome-wide CRISPR-Cas9 loss-of-function screen in differential valine conditions identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. Our findings identify tRNA deregulation as a critical adaptation in the pathogenesis of T-ALL and provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.
    DOI:  https://doi.org/10.1038/s41586-021-04244-1
  19. Nat Immunol. 2022 Jan;23(1): 109-121
    Identification of RIOK2 as a master regulator of human blood cell development.
    Shrestha Ghosh, Mahesh Raundhal, Samuel A Myers, Steven A Carr, Xi Chen, Gregory A Petsko, Laurie H Glimcher.
      Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
    DOI:  https://doi.org/10.1038/s41590-021-01079-w
  20. Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10
    Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
    Dylan Gerard Ryan, Ming Yang, Hiran A Prag, Giovanny Rodriguez Blanco, Efterpi Nikitopoulou, Marc Segarra-Mondejar, Christopher A Powell, Tim Young, Nils Burger, Jan Lj Miljkovic, Michal Minczuk, Michael P Murphy, Alex von Kriegsheim, Christian Frezza.
      The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.
    Keywords:  biochemistry; cell biology; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.72593
  21. Blood. 2021 Dec 21. pii: blood.2021014108. [Epub ahead of print]
    Clonal hematopoiesis associates with improved survival in metastatic colorectal cancer patients from the FIRE-3 trial.
    Christopher Maximilian Arends, Savvina Dimitriou, Arndt Stahler, Raphael Hablesreiter, Paulina M Strzelecka, Catarina M Stein, Marlon Tilgner, Ryunosuke Saiki, Seishi Ogawa, Lars Bullinger, Dominik Paul Modest, Sebastian Stintzing, Volker Heinemann, Frederik Damm.
      
    DOI:  https://doi.org/10.1182/blood.2021014108
  22. Exp Hematol. 2021 Dec 15. pii: S0301-472X(21)00823-7. [Epub ahead of print]
    Transcriptional differences between JAK2-V617F and wild-type bone marrow cells in myeloproliferative neoplasm patients.
    Debra Van Egeren, Baransel Kamaz, Shichen Liu, Maximilian Nguyen, Christopher R Reilly, Maria Kalyva, Daniel J DeAngelo, Ilene Galinsky, Martha Wadleigh, Eric S Winer, Marlise R Luskin, Richard M Stone, Jacqueline S Garcia, Gabriela S Hobbs, Franziska Michor, Isidro Cortes-Ciriano, Ann Mullally, Sahand Hormoz.
      The JAK2-V617F mutation is the most common cause of myeloproliferative neoplasms. While experiments have shown that this gain-of-function mutation is associated with myeloid blood cell expansion and increased production of white cells, red cells and platelets, the transcriptional consequences of the JAK2-V617F mutation in different cellular compartments of the bone marrow have not yet been fully elucidated. To study the direct effects of JAK2-V617F on bone marrow cells in myeloproliferative neoplasm patients, we performed joint single-cell RNA sequencing and JAK2 genotyping on CD34+ enriched cells from 8 patients with newly diagnosed essential thrombocythemia or polycythemia vera. We found that the JAK2-V617F mutation increases the expression of interferon-response genes (e.g., HLAs) and the leptin receptor in hematopoietic progenitor cells. Furthermore, we sequenced a population of CD34-bone marrow monocytes and found the JAK2 mutation increased expression of intermediate monocyte genes and the fibrocyte-associated surface protein SLAMF7 in these cells.
    Keywords:  JAK2-V617F; myeloproliferative neoplasm; single-cell sequencing
    DOI:  https://doi.org/10.1016/j.exphem.2021.12.364
  23. Nat Cancer. 2021 Jul;2(7): 758-772
    Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment.
    Catherine Gutierrez, Aziz M Al'Khafaji, Eric Brenner, Kaitlyn E Johnson, Satyen H Gohil, Ziao Lin, Binyamin A Knisbacher, Russell E Durrett, Shuqiang Li, Salma Parvin, Anat Biran, Wandi Zhang, Laura Rassenti, Thomas J Kipps, Kenneth J Livak, Donna Neuberg, Anthony Letai, Gad Getz, Catherine J Wu, Amy Brock.
      Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding with single-cell RNA sequencing and clonal isolation to comprehensively characterize thousands of clones within heterogeneous populations. Using ClonMapper, we identified subpopulations of a chronic lymphocytic leukemia cell line with distinct clonal compositions, transcriptional signatures and chemotherapy survivorship trajectories; patterns that were also observed in primary human chronic lymphocytic leukemia. The ability to retrieve specific clones before, during and after treatment enabled direct measurements of clonal diversification and durable subpopulation transcriptional signatures. ClonMapper is a powerful multifunctional approach to dissect the complex clonal dynamics of tumor progression and therapeutic response.
    DOI:  https://doi.org/10.1038/s43018-021-00222-8
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