bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–02–11
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
  2. Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study.
  3. Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.
  4. PIEZO1 is essential for the survival and proliferation of acute myeloid leukemia cells.
  5. Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia.
  6. De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors.
  7. LIN28B promotes differentiation of fully transformed AML cells but is dispensable for fetal leukemia suppression.
  8. Clonal hematopoiesis in children with predisposing conditions.
  9. Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM).
  10. The heart of VIALE-A: Cardiac complications of hypomethylating agents and venetoclax in acute myeloid leukaemia.
  11. Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.
  12. New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with JAK inhibitors.
  13. Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.
  14. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients.
  15. Germline predisposition for clonal hematopoiesis.
  16. Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.
  17. Zeb1 maintains long-term adult hematopoietic stem cell function and extramedullary hematopoiesis.
  18. Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study.
  19. Targetable leukemia dependency on noncanonical PI3Kγ signaling.
  20. Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.
  21. SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.
  22. Allogeneic Hematopoietic Cell Transplantation for VEXAS Syndrome: Results of a Multicenter Study of the EBMT.
  23. Two to tango: engineered T cells against AML.
  24. Systematic review and meta-analysis evaluating clinical outcomes in adult acute myeloid leukemia patients with central nervous system involvement.
  25. A machine learning model identifies M3-like subtype in AML based on PML/RARα targets.
  26. Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy.
  1. Blood Cancer Discov. 2024 Feb 08. OF1-OF3
    Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
    David P Steensma.
       SUMMARY: Isocitrate dehydrogenase (IDH)-mutant acute myeloid leukemia (AML) is treatable with inhibitors of mutant IDH and also responds well to combination therapies including venetoclax, but most patients with IDH-mutant AML either never achieve complete remission or relapse because mutant hematopoietic stem cells persist despite treatment. An interesting new study in Blood Cancer Discovery characterizes a specific vulnerability in the mitochondrial oxidative phosphorylation system in preleukemic hematopoietic stem cells from patients with IDH1 mutations that is not present in those with IDH2 mutations; will this susceptibility prove amenable to therapy? See related article by Landberg et al. (10).
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0255
  2. Lancet Haematol. 2024 Feb 02. pii: S2352-3026(23)00367-8. [Epub ahead of print]
    Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study.
    Alex Bataller, Guillermo Montalban-Bravo, Alexandre Bazinet, Yesid Alvarado, Kelly Chien, Sangeetha Venugopal, Jo Ishizawa, Danielle Hammond, Mahesh Swaminathan, Koji Sasaki, Ghayas C Issa, Nicholas J Short, Lucia Masarova, Naval G Daver, Tapan M Kadia, Simona Colla, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Stephany Hendrickson, Farhad Ravandi, Elias Jabbour, Hagop Kantarjian, Guillermo Garcia-Manero.
       BACKGROUND: Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.
    METHODS: We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants.
    FINDINGS: Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.
    INTERPRETATION: This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.
    FUNDING: MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00367-8
  3. J Clin Oncol. 2024 Feb 07. JCO2301061
    Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.
    Eunice S Wang, Aaron D Goldberg, Martin Tallman, Roland B Walter, Chatchada Karanes, Karamjeet Sandhu, Carlos E Vigil, Robert Collins, Vinay Jain, Richard M Stone.
       PURPOSE: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML.
    METHODS: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant.
    RESULTS: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation.
    CONCLUSION: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.
    DOI:  https://doi.org/10.1200/JCO.23.01061
  4. Cancer Med. 2024 Jan;13(2): e6984
    PIEZO1 is essential for the survival and proliferation of acute myeloid leukemia cells.
    Delphine Lebon, Louison Collet, Stefan Djordjevic, Cathy Gomila, Hakim Ouled-Haddou, Jessica Platon, Yohann Demont, Jean-Pierre Marolleau, Alexis Caulier, Loïc Garçon.
       INTRODUCTION: Leukemogenesis is a complex process that interconnects tumoral cells with their microenvironment, but the effect of mechanosensing in acute myeloid leukemia (AML) blasts is poorly known. PIEZO1 perceives and transmits the constraints of the environment to human cells by acting as a non-selective calcium channel, but very little is known about its role in leukemogenesis.
    RESULTS: For the first time, we show that PIEZO1 is preferentially expressed in healthy hematopoietic stem and progenitor cells in human hematopoiesis, and globally overexpressed in AML cells. In AML subtypes, PIEZO1 expression associates with favorable outcomes as better overall (OS) and disease-free survival (DFS). If PIEZO1 is expressed and functional in THP1 leukemic myeloid cell line, its chemical activation doesn't impact the proliferation, differentiation, nor survival of cells. However, the downregulation of PIEZO1 expression dramatically reduces the proliferation and the survival of THP1 cells. We show that PIEZO1 knock-down blocks the cell cycle in G0/G1 phases of AML cells, impairs the DNA damage response pathways, and critically increases cell death by triggering extrinsic apoptosis pathways.
    CONCLUSIONS: Altogether, our results reveal a new role for PIEZO1 mechanosensing in the survival and proliferation of leukemic blasts, which could pave the way for new therapeutic strategies to target AML cells.
    Keywords:  PIEZO1; acute myeloid leukemia; apoptosis; cell cycle; proliferation; survival
    DOI:  https://doi.org/10.1002/cam4.6984
  5. Cancers (Basel). 2024 Jan 29. pii: 569. [Epub ahead of print]16(3):
    Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia.
    Sydney Fobare, Ola A Elgamal, Mark Wunderlich, Emily Stahl, Abeera Mehmood, Casie Furby, James R Lerma, Thomas M Sesterhenn, Jianmin Pan, Jayesh Rai, Megan E Johnstone, Amina Abdul-Aziz, Mariah L Johnson, Shesh N Rai, John C Byrd, Erin Hertlein.
       BACKGROUND: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models.
    METHODS: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted.
    RESULTS: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice.
    CONCLUSIONS: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.
    Keywords:  EZH2; acute myeloid leukemia; differentiation therapy
    DOI:  https://doi.org/10.3390/cancers16030569
  6. Am J Hematol. 2024 Feb 05.
    De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors.
    Tomas Hornak, Jiri Mayer, Petra Cicatkova, Lukas Semerad, Anezka Kvetkova, Hana Klamova, Edgar Faber, Petra Belohlavkova, Michal Karas, Lukas Stejskal, Eduard Cmunt, Olga Cerna, Dana Srbova, Hana Zizkova, Lucia Vrablova, Ivana Skoumalova, Jaroslava Voglova, Tereza Jurkova, Marika Chrapava, Tomas Jurcek, Ivana Jeziskova, Marie Jarosova, Katerina Machova Polakova, Tomas Papajik, Pavel Zak, Pavel Jindra, Daniela Zackova.
      Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR).
    DOI:  https://doi.org/10.1002/ajh.27229
  7. Leukemia. 2024 Feb 06.
    LIN28B promotes differentiation of fully transformed AML cells but is dispensable for fetal leukemia suppression.
    Yanan Li, Jonny Mendoza-Castrejon, Riddhi M Patel, Emily B Casey, Elisabeth Denby, David Bryder, Jeffrey A Magee.
      
    DOI:  https://doi.org/10.1038/s41375-024-02167-0
  8. Semin Hematol. 2024 Jan 14. pii: S0037-1963(24)00006-4. [Epub ahead of print]
    Clonal hematopoiesis in children with predisposing conditions.
    Enrico Attardi, Seth J Corey, Marcin W Wlodarski.
      Clonal hematopoiesis in children and young adults differs from that occuring in the older adult population. A variety of stressors drive this phenomenon, sometimes independent of age-related processes. For the purposes of this review, we adopt the term clonal hematopoiesis in predisposed individuals (CHIPI) to differentiate it from classical, age-related clonal hematopoiesis of indeterminate potential (CHIP). Stress-induced CHIPI selection can be extrinsic, such as following immunologic, infectious, pharmacologic, or genotoxic exposures, or intrinsic, involving germline predisposition from inherited bone marrow failure syndromes. In these conditions, clonal advantage relates to adaptations allowing improved cell fitness despite intrinsic defects affecting proliferation and differentiation. In certain contexts, CHIPI can improve competitive fitness by compensating for germline defects; however, the downstream effects of clonal expansion are often unpredictable - they may either counteract the underlying pathology or worsen disease outcomes. A more complete understanding of how CHIPI arises in young people can lead to the definition of preleukemic states and strategies to assess risk, surveillance, and prevention to leukemic transformation. Our review summarizes current research on stress-induced clonal dynamics in individuals with germline predisposition syndromes.
    Keywords:  clonal hematopoiesis in predisposed individuals; inherited bone marrow failure syndromes; pediatric clonal hematopoiesis; somatic genetic rescue
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.005
  9. Blood Cancer J. 2024 Feb 05. 14(1): 25
    Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM).
    Christopher P Mill, Warren C Fiskus, Courtney D DiNardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla.
      Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
    DOI:  https://doi.org/10.1038/s41408-024-00981-4
  10. Br J Haematol. 2024 Feb 09.
    The heart of VIALE-A: Cardiac complications of hypomethylating agents and venetoclax in acute myeloid leukaemia.
    Shyam A Patel.
      As we commemorate 50 years since the introduction of classical 7 + 3 induction chemotherapy for acute myeloid leukaemia (AML), we also embark upon new territory with the advent of novel targeted therapeutics, including BH3 mimetics. To date, we do not have much large-scale longitudinal data regarding the toxicities of such novel therapies. Johnson et al. perform a comprehensive analysis of cardiac toxicities with hypomethylating agents and venetoclax and offer valuable insight into risk-benefit analysis when considering front-line therapy for AML. Commentary on: Johnson et al. Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19325.
    Keywords:  VIALE-A; acute myeloid leukemia; cardiac events
    DOI:  https://doi.org/10.1111/bjh.19336
  11. Br J Haematol. 2024 Feb 04.
    Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.
    Isla M Johnson, Omer Karrar, Masooma Rana, Moazah Iftikhar, Sunny Chen, Kristen McCullough, Antoine N Saliba, Aref Al-Kali, Hassan Alkhateeb, Kebede Begna, Mark Litzow, William J Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Joerg Hermann, Ayalew Tefferi, Naseema Gangat.
      Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.
    Keywords:  heart failure; leukaemia; pericarditis; venetoclax
    DOI:  https://doi.org/10.1111/bjh.19325
  12. Am J Hematol. 2024 Feb 08.
    New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with JAK inhibitors.
    Naseema Gangat, Ayalew Tefferi.
      Ruxolitinib in combination with navitoclax or pelabresib in myelofibrosis: activity in JAKi-naïve patients.
    DOI:  https://doi.org/10.1002/ajh.27248
  13. Am J Hematol. 2024 Feb 05.
    Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.
    Elias Jabbour, Gerhard Zugmaier, Vaibhav Agrawal, Pilar Martínez-Sánchez, José J Rifón Roca, Ryan D Cassaday, Boris Böll, Anita Rijneveld, Maher Abdul-Hay, Françoise Huguet, Thomas Cluzeau, Mar Tormo Díaz, Vladan Vucinic, José González-Campos, Alessandro Rambaldi, Stefan Schwartz, Céline Berthon, Jesús María Hernández-Rivas, Paul R Gordon, Monika Brüggemann, Ali Hamidi, Yuqi Chen, Hansen L Wong, Bharat Panwar, Yuliya Katlinskaya, Ana Markovic, Hagop Kantarjian.
      Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 μg once daily (QD) for week 1 and 500 μg three times weekly (TIW) thereafter (250 μg/500 μg) or (2) 500 μg QD for week 1 and 1000 μg TIW thereafter (500 μg/1000 μg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 μg/500 μg dose and 13 at 500 μg/1000 μg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 μg/500 μg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 μg/1000 μg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.
    DOI:  https://doi.org/10.1002/ajh.27227
  14. Br J Haematol. 2024 Feb 07.
    Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients.
    Vincent Alcazer, Stéphane Morisset, Delphine Rea, Laurence Legros, Stéphanie Dulucq, Sandrine Hayette, Jean-Michel Cayuela, Françoise Huguet, François-Xavier Mahon, Gabriel Etienne, Franck E Nicolini.
      
    DOI:  https://doi.org/10.1111/bjh.19330
  15. Semin Hematol. 2024 Jan 14. pii: S0037-1963(24)00005-2. [Epub ahead of print]
    Germline predisposition for clonal hematopoiesis.
    Yasuo Kubota, Aaron D Viny.
      Clonal hematopoiesis (CH) is an entity hallmarked by skewed hematopoiesis with persistent overrepresentation of cells from a common stem/progenitor lineage harboring single-nucleotide variants and/or insertions/deletions. CH is a common and age-related phenomenon that is associated with an increased risk of hematological malignancies, cardiovascular disease, and all-cause mortality. While CH is a term of the hematological aspect, there exists a complex interaction with other organ systems, especially the cardiovascular system. The strongest factor in the development of CH is aging, however, other multiple factors also affect the development of CH including lifestyle-related factors and co-morbid diseases. In recent years, germline genetic factors have been linked to CH risk. In this review, we synthesize what is currently known about how genetic variation affects the risk of CH, how this genetic architecture intersects with myeloid neoplasms, and future prospects for CH.
    Keywords:  CH; Germline predisposition; Myeloid malignancies
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.007
  16. Nat Commun. 2024 Feb 05. 15(1): 1090
    Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.
    Amy Dawson, Martha M Zarou, Bodhayan Prasad, Joana Bittencourt-Silvestre, Désirée Zerbst, Ekaterini Himonas, Ya-Ching Hsieh, Isabel van Loon, Giovanny Rodriguez Blanco, Angela Ianniciello, Zsombor Kerekes, Vaidehi Krishnan, Puneet Agarwal, Hassan Almasoudi, Laura McCluskey, Lisa E M Hopcroft, Mary T Scott, Pablo Baquero, Karen Dunn, David Vetrie, Mhairi Copland, Ravi Bhatia, Seth B Coffelt, Ong Sin Tiong, Helen Wheadon, Sara Zanivan, Kristina Kirschner, G Vignir Helgason.
      Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
    DOI:  https://doi.org/10.1038/s41467-024-45471-0
  17. Exp Hematol. 2024 Feb 07. pii: S0301-472X(24)00036-5. [Epub ahead of print] 104177
    Zeb1 maintains long-term adult hematopoietic stem cell function and extramedullary hematopoiesis.
    Alhomidi Almotiri, Ali Abdelfattah, Elis Storch, Marc P Stemmler, Simone Brabletz, Thomas Brabletz, Neil P Rodrigues.
      Emerging evidence implicates the epithelial-mesenchymal transition (EMT) transcription factor Zeb1 as a critical regulator of hematopoietic stem cell (HSC) differentiation. Whether Zeb1 regulates long-term maintenance of HSC function remains an open question. Through use of an inducible Mx-1 Cre mouse model that deletes conditional Zeb1 alleles in the adult hematopoietic system, we found that mice engineered to be deficient in Zeb1 for 32 weeks displayed expanded immunophenotypically defined adult HSCs and multi-potent progenitors associated with increased abundance of lineage-biased/balanced HSC subsets and augmented cell survival characteristics. During hematopoietic differentiation, persistent Zeb1 loss increased B-cells in the bone marrow and spleen and decreased monocyte generation in the peripheral blood. Using competitive transplantation experiments, we found that HSCs from adult mice with long-term Zeb1 deletion displayed a cell autonomous defect in multi-lineage differentiation capacity. Long-term Zeb1 loss perturbed extramedullary hematopoiesis characterized by increased splenic weight and a paradoxical reduction in splenic cellularity that was accompanied by HSC exhaustion, lineage specific defects and an accumulation of aberrant, pre-leukemic like c-kit+CD16/32+ progenitors. Loss of Zeb1 for up to 42 weeks can lead to progressive splenomegaly and an accumulation of Gr-1+Mac-1+ cells, further supporting the notion that long-term expression of Zeb1 suppresses pre-leukemic activity. Thus, sustained Zeb1 deletion disrupts HSC functionality in vivo and impairs regulation of extramedullary hematopoiesis with potential implications for tumor suppressor functions of Zeb1 in myeloid neoplasms.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104177
  18. Leukemia. 2024 Feb 06.
    Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study.
    James T England, Natasha Szuber, Shireen Sirhan, Tom Dunne, Sonia Cerquozzi, Madeleine Hill, Pierre J A Villeneuve, Jenny M Ho, Bekim Sadikovic, Pratibha Bhai, Nupur Krishnan, Sebastian Dowhanik, Chris Hillis, Jose-Mario Capo-Chichi, Hubert Tsui, Verna Cheung, Karine Gauthier, Hassan Sibai, Marta B Davidson, Aniket Bankar, Rouslan Kotchetkov, Vikas Gupta, Dawn Maze.
      Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.
    DOI:  https://doi.org/10.1038/s41375-024-02155-4
  19. bioRxiv. 2023 Dec 15. pii: 2023.12.15.571909. [Epub ahead of print]
    Targetable leukemia dependency on noncanonical PI3Kγ signaling.
    Qingyu Luo, Evangeline G Raulston, Miguel A Prado, Xiaowei Wu, Kira Gritsman, Kezhi Yan, Christopher A G Booth, Ran Xu, Peter van Galen, John G Doench, Shai Shimony, Henry W Long, Donna S Neuberg, Joao A Paulo, Andrew A Lane.
      Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and activation of phosphoinositide 3-kinase regulatory subunit 5 ( PIK3R5 ), which encodes a regulatory subunit of PI3Kγ and stabilizes the active enzymatic complex. Mechanistically, we identify p21 (RAC1) activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of Akt kinase. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5 , either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals a targetable dependency on PI3Kγ/PAK1 signaling that is amenable to near-term evaluation in patients with acute leukemia.
    DOI:  https://doi.org/10.1101/2023.12.15.571909
  20. Blood Cancer J. 2024 Feb 09. 14(1): 28
    Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.
    Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt-Dalbøge, Trine Alma Knudsen, Marie Hvelplund Kristiansen, Anders Lindholm Sørensen, Troels Wienecke, Morten Andersen, Johnny T Ottesen, Johanne Gudmand-Høyer, Jordan Andrew Snyder, Mikkel Porsborg Andersen, Christian Torp-Pedersen, Henrik Enghusen Poulsen, Thomas Stiehl, Hans Carl Hasselbalch, Christina Ellervik.
      The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.
    DOI:  https://doi.org/10.1038/s41408-024-00994-z
  21. Nat Cell Biol. 2024 Feb 06.
    SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.
    Xi Xu, Yanhui Yu, Wenwen Zhang, Weiwei Ma, Chong He, Guo Qiu, Xinyi Wang, Qiong Liu, Minyi Zhao, Jiayi Xie, Fang Tao, John M Perry, Qifa Liu, Shuan Rao, Xunlei Kang, Meng Zhao, Linjia Jiang.
      Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.
    DOI:  https://doi.org/10.1038/s41556-024-01349-3
  22. Blood Adv. 2024 Feb 08. pii: bloodadvances.2023012478. [Epub ahead of print]
    Allogeneic Hematopoietic Cell Transplantation for VEXAS Syndrome: Results of a Multicenter Study of the EBMT.
    Carmelo Gurnari, Linda Koster, Laurien Greetje Antoinette Baaij, Mael Heiblig, Ibrahim Yakoub-Agha, Matthew Collin, Jakob R Passweg, Claude-Eric Bulabois, Anjum Bashir Khan, Michael Loschi, Fabrizio Carnevale-Schianca, Elena Crisà, Daniela Caravelli, Jürgen Kuball, Francesco Saraceni, Attilio Olivieri, Alessandro Rambaldi, Austin G Kulasekararaj, Patrick Hayden, Manuela Badoglio, Francesco Onida, Christof Scheid, Franco Franceschini, Arsene Mékinian, Sinisa Savic, Maria Teresa Voso, Joanna Drozd-Sokolowska, John Snowden, Kavita Raj, Tobias Alexander, Marie Robin, Raffaela Greco, Donal P McLornan.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023012478
  23. Blood. 2024 Feb 08. 143(6): 476-478
    Two to tango: engineered T cells against AML.
    Caroline Arber.
      
    DOI:  https://doi.org/10.1182/blood.2023023004
  24. Leuk Res. 2024 Feb 06. pii: S0145-2126(24)00018-3. [Epub ahead of print]137 107452
    Systematic review and meta-analysis evaluating clinical outcomes in adult acute myeloid leukemia patients with central nervous system involvement.
    Hannah Goulart, Dahniel Sastow, Erin Moshier, Lily Martin, John Mascarenhas, Douglas Tremblay.
      Patients with acute myeloid leukemia (AML) may experience extramedullary involvement when disease is present outside of the blood and bone marrow. In particular, the presence of central nervous system (CNS) involvement has traditionally been thought of as a poor prognostic factor. In the presently available literature, there is a paucity of conclusive data surrounding CNS AML given its rarity and lack of unified screening practices. Thus, we performed a systematic review and meta-analysis in order to more definitively characterize survival outcomes in this patient population. In this meta-analysis, we evaluated survival outcomes and response rates from clinical studies on patients with AML stratified by the presence of CNS involvement. Twelve studies were included in the meta-analysis with a resulting hazard ratio (HR) for overall survival (OS) of 1.34 with a 95 % CI of 1.14 to 1.58. These findings suggest that CNS involvement in adult patients with AML is associated with an increased hazard of mortality compared to those patients without CNS involvement. As such, CNS involvement should be viewed as negative prognostic marker, and attention should be made to ensure prompt identification and treatment of patients who experience this complication.
    Keywords:  AML; Acute myeloid leukemia; CNS leukemia; CNS relapse
    DOI:  https://doi.org/10.1016/j.leukres.2024.107452
  25. iScience. 2024 Feb 16. 27(2): 108947
    A machine learning model identifies M3-like subtype in AML based on PML/RARα targets.
    Tingting Shao, Jianing Li, Minghai Su, Changbo Yang, Yingying Ma, Chongwen Lv, Wei Wang, Yunjin Xie, Gang Xu, Ce Shi, Xinying Zhou, Huitao Fan, Yongsheng Li, Juan Xu.
      The typical genomic feature of acute myeloid leukemia (AML) M3 subtype is the fusion event of PML/RARα, and ATRA/ATO-based combination therapy is current standard treatment regimen for M3 subtype. Here, a machine-learning model based on expressions of PML/RARα targets was developed to identify M3 patients by analyzing 1228 AML patients. Our model exhibited high accuracy. To enable more non-M3 AML patients to potentially benefit from ATRA/ATO therapy, M3-like patients were further identified. We found that M3-like patients had strong GMP features, including the expression patterns of M3 subtype marker genes, the proportion of myeloid progenitor cells, and deconvolution of AML constituent cell populations. M3-like patients exhibited distinct genomic features, low immune activity and better clinical survival. The initiative identification of patients similar to M3 subtype may help to identify more patients that would benefit from ATO/ATRA treatment and deepen our understanding of the molecular mechanism of AML pathogenesis.
    Keywords:  Genomics; Machine learning; Medical science
    DOI:  https://doi.org/10.1016/j.isci.2024.108947
  26. Cancer Discov. 2024 Feb 05.
    Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy.
    Yaniv Kazansky, Daniel Cameron, Helen S Mueller, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Yasumichi Kuwahara, Romel Somwar, Marc Ladanyi, Rui Qu, Elisa de Stanchina, Filemon S Dela Cruz, Andrew L Kung, Mrinal M Gounder, Alex Kentsis.
      Epigenetic dependencies have become evident in many cancers. Based on antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors. We found distinct acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, suggests a general mechanism for effective therapy, and provides prospective biomarkers for therapy stratification, including PRICKLE1. Based on this, we develop a combination strategy to circumvent tazemetostat resistance using bypass targeting of AURKB. This offers a paradigm for rational epigenetic combination therapy suitable for translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0110
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