bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–02–18
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.
  2. Post induction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission.
  3. Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.
  4. Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses.
  5. Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.
  6. Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.
  7. Targetable genetic abnormalities in patients with acute myeloblastic leukemia across age groups.
  8. Human ASXL1-mutant hematopoiesis is driven by a truncated protein associated with aberrant de-ubiquitination of H2AK119.
  9. Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.
  10. Secondary acute myeloid leukemia and de novo acute myeloid leukemia with myelodysplasia-related changes - close or complete strangers?
  11. Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.
  12. Cohesin loss and MLL-AF9 are not synthetic lethal in murine hematopoietic stem and progenitor cells.
  13. The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia.
  14. Charting a path through resistance: HDAC inhibitors for TP53-mutated B-acute lymphoblastic leukemia.
  15. Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.
  16. Venetoclax resistance in acute myeloid leukaemia-Clinical and biological insights.
  17. Menin dependence: UBTF-ITD AML joins the club.
  18. Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation.
  19. TET2 mutations contribute to adverse prognosis in acute myeloid leukemia (AML): results from a comprehensive analysis of 502 AML cases and the Beat AML public database.
  20. Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.
  21. SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
  22. Venetoclax-based therapy for relapsed or refractory acute myeloid leukemia: latest updates from the 2023 ASH annual meeting.
  23. Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia.
  24. Blood and Guts: How the Intestinal Microbiome Shapes Hematopoiesis and Treatment of Hematologic Disease.
  25. Promoter-centred chromatin interactions associated with EVI1 expression in EVI1+3q- myeloid leukaemia cells.
  26. ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion.
  27. Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.
  1. Am J Hematol. 2024 Feb 11.
    Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.
    Yasmin Abaza, Eric S Winer, Guru Subramanian Guru Murthy, Rory M Shallis, Andrew H Matthews, Talha Badar, Emily M Geramita, Vamsi K Kota, Alok Swaroop, Peter Doukas, Danielle Bradshaw, Irene B Helenowski, Yingzhe Liu, Hui Zhang, Annie Im, Mark R Litzow, Alexander E Perl, Ehab Atallah, Jessica K Altman.
      Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.
    DOI:  https://doi.org/10.1002/ajh.27231
  2. Blood. 2024 Feb 16. pii: blood.2023023096. [Epub ahead of print]
    Post induction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission.
    Jad Othman, Nicola Potter, Adam Ivey, Jelena Jovanovic, Manohursingh Runglall, Sylvie D Freeman, Amanda Frances Gilkes, Ian Thomas, Sean Johnson, Joanna Canham, James Durrell Cavenagh, Panagiotis Kottaridis, Claire Arnold, Hans Beier Ommen, Ulrik Malthe Overgaard, Mike Dennis, Alan K Burnett, Charlotte S Wilhelm-Benartzi, Richard Dilon, Nigel H Russell.
      Selection of patients with NPM1 mutated AML for allogeneic transplant in 1st complete remission (CR1-allo) remains controversial due to a lack of robust data. Consequently, some centres consider baseline FLT3-ITD an indication for transplant and others rely on measurable residual disease (MRD) status. Using prospective data from the UK NCRI AML17 and AML19 studies, we examined the impact of CR1-allo according to peripheral blood NPM1 MRD status measured by RT-qPCR after 2 courses of induction chemotherapy. Of 737 patients achieving remission, MRD was positive in 19%. CR1-allo was performed in 46% of MRD+ and 17% of MRD- patients. We observed significant heterogeneity of overall survival (OS) benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD+ patients (3y OS with CR1-allo 61% vs 24% without, HR 0.39, 95%CI 0.24-0.64, p<0.001) but no benefit for MRD- patients (3y OS 79% vs 82%, HR 0.82, 95%CI 0.50-1.33, p=0.4). Restricting analysis to patients with co-existing FLT3-ITD, again CR1-allo only improved OS for MRD+ patients (3y OS 45% vs 18%; compared to 83% vs 76% if MRD-); no interaction with FLT3 allelic ratio was observed. Post-induction molecular MRD reliably identifies those patients who benefit from allogeneic transplant in first remission. AML17 ISRCTN55675535 AML19 ISRCTN78449203.
    DOI:  https://doi.org/10.1182/blood.2023023096
  3. EMBO Mol Med. 2024 Feb 14.
    Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.
    Jan Mueller, Roman R Schimmer, Christian Koch, Florin Schneiter, Jonas Fullin, Veronika Lysenko, Christian Pellegrino, Nancy Klemm, Norman Russkamp, Renier Myburgh, Laura Volta, Alexandre Pa Theocharides, Kari J Kurppa, Benjamin L Ebert, Timm Schroeder, Markus G Manz, Steffen Boettcher.
      TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
    Keywords:  AML; CAR T-Cell Therapy; Mevalonate Pathway; TP53 Mutations
    DOI:  https://doi.org/10.1038/s44321-024-00024-2
  4. Leukemia. 2024 Feb 15.
    Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses.
    Jeppe F Severens, E Onur Karakaslar, Bert A van der Reijden, Elena Sánchez-López, Redmar R van den Berg, Constantijn J M Halkes, Peter van Balen, Hendrik Veelken, Marcel J T Reinders, Marieke Griffioen, Erik B van den Akker.
      Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.
    DOI:  https://doi.org/10.1038/s41375-024-02137-6
  5. Am J Hematol. 2024 Feb 11.
    Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.
    Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Michael J Thirman, Jacqueline S Garcia, Hartmut Döhner, Christian Récher, Walter Fiedler, Kazuhito Yamamoto, Jianxiang Wang, Sung-Soo Yoon, Ofir Wolach, Su-Peng Yeh, Brian Leber, Jordi Esteve, Jiri Mayer, Kimmo Porkka, Árpád Illés, Roberto M Lemoli, Mehmet Turgut, Grace Ku, Catherine Miller, Ying Zhou, Meng Zhang, Brenda Chyla, Jalaja Potluri, Courtney D DiNardo.
      Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.
    DOI:  https://doi.org/10.1002/ajh.27246
  6. Nat Commun. 2024 Feb 14. 15(1): 1359
    Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.
    Sophie G Kellaway, Sandeep Potluri, Peter Keane, Helen J Blair, Luke Ames, Alice Worker, Paulynn S Chin, Anetta Ptasinska, Polina K Derevyanko, Assunta Adamo, Daniel J L Coleman, Naeem Khan, Salam A Assi, Anja Krippner-Heidenreich, Manoj Raghavan, Peter N Cockerill, Olaf Heidenreich, Constanze Bonifer.
      Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
    DOI:  https://doi.org/10.1038/s41467-024-45691-4
  7. Am J Hematol. 2024 Feb 15.
    Targetable genetic abnormalities in patients with acute myeloblastic leukemia across age groups.
    Alex Bataller, Courtney D DiNardo, Alexandre Bazinet, Naval G Daver, Abhishek Maiti, Gautam Borthakur, Nicholas Short, Koji Sasaki, Elias J Jabbour, Ghayas C Issa, Naveen Pemmaraju, Musa Yilmaz, Guillermo Montalban-Bravo, Sanam Loghavi, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Tapan M Kadia.
      Incidence of potential targetable genetic abnormalities by age in AML.
    DOI:  https://doi.org/10.1002/ajh.27236
  8. Blood Cancer Discov. 2024 Feb 15.
    Human ASXL1-mutant hematopoiesis is driven by a truncated protein associated with aberrant de-ubiquitination of H2AK119.
    Thomas Kohnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti.
      Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in pre-malignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant specific therapeutic vulnerability both in pre-malignant CH and myeloid malignancy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0235
  9. Exp Hematol. 2024 Feb 08. pii: S0301-472X(24)00037-7. [Epub ahead of print] 104178
    Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.
    Taylor B Collins, Angelo B A Laranjeira, Tim Kong, Mary C Fulbright, Daniel A C Fisher, Christopher M Sturgeon, Luis F Z Batista, Stephen T Oh.
      Myeloproliferative neoplasms (MPN) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induce a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated MPN disease burden including leukemic engraftment and splenomegaly in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only to primary MPN samples harboring ASXL1 mutations. Lastly, treatment of CD34+ hematopoietic/stem progenitor cells with PRMT6 inhibitor, EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.
    Keywords:  ASXL1; Erythrocytosis; JAK2; Myeloproliferative neoplasms; PRMT6
    DOI:  https://doi.org/10.1016/j.exphem.2024.104178
  10. Folia Med (Plovdiv). 2023 Oct 31. 65(5): 728-736
    Secondary acute myeloid leukemia and de novo acute myeloid leukemia with myelodysplasia-related changes - close or complete strangers?
    Milan Jagurinoski, Yanitsa Davidkova, Milena Stojcov-Jagurinoska, Gueorgui Balatzenko, Branimir Spassov, Margarita Guenova.
       AIM: To compare the main features of patients with secondary acute myeloid leukemias (AMLs) after post-myelodysplastic syndrome (AML-post-MDS) or post-myeloproliferative neoplasms (AML-post-MPN) and myeloid blast crisis of chronic myeloid leukemia (CML-BC) vs. de novoAMLs with myelodysplastic characteristics (dn-AML-MDS).
    Keywords:  acute myeloid leukemia blast crisis myelodysplasia myeloproliferative disorder
    DOI:  https://doi.org/10.3897/folmed.65.e98404
  11. Am J Hematol. 2024 Feb 15.
    Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.
    Nico Gagelmann, Gabriela S Hobbs, Edoardo Campodonico, Grzegorz Helbig, Polona Novak, Thomas Schroeder, Artur Schneider, Christina Rautenberg, Hans Christian Reinhardt, Linette Bosques, Michael Heuser, Victoria Panagiota, Felicitas Thol, Carmelo Gurnari, Jaroslaw P Maciejewski, Fabio Ciceri, Kristin Rathje, Marie Robin, Simona Pagliuca, Marie-Thérèse Rubio, Vanderson Rocha, Vaneuza Funke, Nelson Hamerschlak, Rachel Salit, Bart L Scott, Fernando Duarte, Iwona Mitrus, Tomasz Czerw, Raffaella Greco, Nicolaus Kröger.
      Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.
    DOI:  https://doi.org/10.1002/ajh.27252
  12. Res Sq. 2024 Jan 29. pii: rs.3.rs-3894962. [Epub ahead of print]
    Cohesin loss and MLL-AF9 are not synthetic lethal in murine hematopoietic stem and progenitor cells.
    Alison Meyer, Cary Stelloh, Nan Zhu, Sridhar Rao.
      Objective As cohesin mutations are rarely found in MLL-rearranged acute myeloid leukemias, we investigated the potential synthetic lethality between cohesin mutations and MLL-AF9 using murine hematopoietic stem and progenitor cells. Results Contrary to our hypothesis, a complete loss of Stag2 or haploinsufficiency of Smc3 were well tolerated in MLL-AF9-expressing hematopoietic stem and progenitor cells. Minimal effect of cohesin subunit loss on the in vitro self-renewal of MLL-AF9-expressing cells was observed. Despite the differing mutational landscapes of cohesin-mutated and MLL fusion AMLs, previous studies showed that cohesin and MLL fusion mutations similarly drive abnormal self-renewal through HOXA gene upregulation. The utilization of a similar mechanism suggests that little selective pressure exists for the acquisition of cohesin mutations in AMLs expressing MLL fusions, explaining their lack of co-occurrence. Our results emphasize the importance of using genetic models to test suspected synthetic lethality and suggest that a lack of co-occurrence may instead point to a common mechanism of action between two mutations.
    DOI:  https://doi.org/10.21203/rs.3.rs-3894962/v1
  13. Leukemia. 2024 Feb 16.
    The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia.
    Shan Lin, Constanze Schneider, Angela H Su, Gabriela Alexe, David E Root, Kimberly Stegmaier.
      
    DOI:  https://doi.org/10.1038/s41375-024-02178-x
  14. Haematologica. 2024 Feb 15.
    Charting a path through resistance: HDAC inhibitors for TP53-mutated B-acute lymphoblastic leukemia.
    Eitan Kugler.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284796
  15. Nat Cardiovasc Res. 2024 Jan;3(1): 60-75
    Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.
    Trevor P Fidler, Andrew Dunbar, Eunyoung Kim, Brian Hardaway, Jessica Pauli, Chenyi Xue, Sandra Abramowicz, Tong Xiao, Kavi O'Connor, Nadja Sachs, Nan Wang, Lars Maegdefessel, Ross Levine, Muredach Reilly, Alan R Tall.
      Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr-/- mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1β antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF during plaque regression promoted fibroblast accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.
    DOI:  https://doi.org/10.1038/s44161-023-00405-9
  16. Br J Haematol. 2024 Jan 31.
    Venetoclax resistance in acute myeloid leukaemia-Clinical and biological insights.
    Boaz Nachmias, Shlomzion Aumann, Arnon Haran, Aaron D Schimmer.
      Venetoclax, an oral BCL-2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax is the current standard of care for elderly and patient's ineligible for aggressive therapies. However, venetoclax is being increasingly used with aggressive chemotherapy regimens both in the front line and in the relapse setting. Our growing experience and intensive research demonstrate that certain genetic abnormalities are associated with venetoclax sensitivity, while others with resistance, and that resistance can emerge during treatment leading to disease relapse. In the current review, we provide a summary of the known mechanisms of venetoclax cytotoxicity, both regarding the inhibition of BCL-2-mediated apoptosis and its effect on cell metabolism. We describe how these pathways are linked to venetoclax resistance and are associated with specific mutations. Finally, we provide the rationale for novel drug combinations in current and future clinical trials.
    Keywords:  acute myeloid leukaemia; drug resistance; venetoclax
    DOI:  https://doi.org/10.1111/bjh.19314
  17. Blood. 2024 Feb 15. 143(7): 567-569
    Menin dependence: UBTF-ITD AML joins the club.
    Kathrin M Bernt.
      
    DOI:  https://doi.org/10.1182/blood.2023023041
  18. Circulation. 2024 Feb 15.
    Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation.
    Amy Erica Lin, Aneesh C Bapat, Ling Xiao, Abhishek Niroula, Jianchuan Ye, Waihay J Wong, Mridul Agrawal, Christopher J Farady, Andreas Boettcher, Christopher B Hergott, Marie McConkey, Patricio Flores-Bringas, Veronica Shkolnik, Alexander G Bick, David Milan, Pradeep Natarajan, Peter Libby, Patrick T Ellinor, Benjamin L Ebert.
       BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored.
    METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1β (interleukin 1β) or IL-6 (interleukin 6).
    RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atria arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1β or IL-6.
    CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.
    Keywords:  CHIP; NLRP3; atrial fibrillation; clonal hematopoiesis; inflammasome; somatic mutation
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065597
  19. Clin Exp Med. 2024 Feb 13. 24(1): 35
    TET2 mutations contribute to adverse prognosis in acute myeloid leukemia (AML): results from a comprehensive analysis of 502 AML cases and the Beat AML public database.
    Xin'an Pan, Yingjun Chang, Guorui Ruan, Songhai Zhou, Hao Jiang, Qian Jiang, Xiaojun Huang, Xiao-Su Zhao.
      Despite the high incidence of tet methylcytosine dioxygenase 2 (TET2) mutations in acute myeloid leukemia (AML), the prognostic implications of these mutations in three AML risk groups based on the 2022 ELN AML risk classification are still unclear. A total of 502 consecutive de novo AML patients who had next-generation sequencing data available between March 2011 and July 2021 at the Peking University Institute of Hematology were enrolled in this study. Univariate and multivariate Cox regression analyses were performed to explore the prognostic impact of TET2 mutations in the above cohort and the Beat AML cohort. Of the 502 total AML patients, 76 (15.1%) carried TET2 mutations. Multivariate analysis revealed TET2 mutations as independent risk factor for overall survival (OS) in both the total AML cohort (OR = 1.649, p = 0.009) and in the 2022 ELN intermediate-risk cohort (HR = 1.967, p = 0.05). Analysis of RNA-seq data from the Beat AML study revealed 1042 differentially expressed genes (DEGs) between the TET2-mutant and TET2 wild-type groups. The results of enrichment analysis indicated the DEGs to be notably enriched in categories related to the PI3K-Akt signaling pathway. Collectively, our findings indicate that mutations in TET2 are prognostically disadvantageous in AML patients. Assessment of TET2 mutational status contributes to the stratification of intermediate-risk AML patients. Multiple genes and pathways of potential therapeutic relevance may be differentially modulated by TET2 mutations in AML.
    Keywords:  AML Beat database; Acute myeloid leukemia; Bioinformatics analysis; Prognosis; RNA sequencing; TET2 mutations
    DOI:  https://doi.org/10.1007/s10238-024-01297-0
  20. Eur J Med Chem. 2024 Jan 26. pii: S0223-5234(24)00034-5. [Epub ahead of print]267 116154
    Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.
    Julia Velez, Brandon Dale, Kwang-Su Park, H Ümit Kaniskan, Xufen Yu, Jian Jin.
      Aberrant expression of EZH2, the main catalytic subunit of PRC2, has been implicated in numerous cancers, including leukemia, breast, and prostate. Recent studies have highlighted non-catalytic oncogenic functions of EZH2, which EZH2 catalytic inhibitors cannot attenuate. Therefore, proteolysis-targeting chimera (PROTAC) degraders have been explored as an alternative therapeutic approach to suppress both canonical and non-canonical oncogenic activity. Here we present MS8847, a novel, highly potent EZH2 PROTAC degrader that recruits the E3 ligase von Hippel-Lindau (VHL). MS8847 degrades EZH2 in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Notably, MS8847 induces superior EZH2 degradation and anti-proliferative effects in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells compared to previously published EZH2 PROTAC degraders. Moreover, MS8847 degrades EZH2 and inhibits cell growth in triple-negative breast cancer (TNBC) cell lines, displays efficacy in a 3D TNBC in vitro model, and has a pharmacokinetic (PK) profile suitable for in vivo efficacy studies. Overall, MS8847 is a valuable chemical tool for the biomedical community to investigate canonical and non-canonical oncogenic functions of EZH2.
    Keywords:  Acute myeloid leukemia; Degrader; EZH2; Non-canonical function; PROTAC; Proteolysis-targeting chimera; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116154
  21. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]
    SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
    Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.
      SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
    Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
  22. Exp Hematol Oncol. 2024 Feb 16. 13(1): 17
    Venetoclax-based therapy for relapsed or refractory acute myeloid leukemia: latest updates from the 2023 ASH annual meeting.
    Xubo Gong, Xin He, Lin Wang, Teng Yu, Weiwei Liu, Huiying Xu, Lan Jin, Xiang Li, Bin Zhang, Zhihua Tao, Wenbin Qian.
      Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) often exhibit limited responses to traditional chemotherapy, resulting in poor prognosis. The combination of venetoclax (VEN) with hypomethylating agents has been established as the standard treatment for elderly or medically unfit AML patients unable to undergo intensive chemotherapy. Despite this, the availability of novel VEN-based therapies specifically tailored for those with R/R AML remains scarce. Here, we provide a comprehensive overview of the latest data presented at the 65th American Society of Hematology Annual Meeting, shedding light on the progress and efficacy of VEN-based therapies for R/R AML.
    Keywords:  Acute myeloid leukemia; Hypomethylating agents; Venetoclax
    DOI:  https://doi.org/10.1186/s40164-024-00486-7
  23. Nat Commun. 2024 Feb 16. 15(1): 1423
    Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia.
    Wen Jin, Yuting Dai, Li Chen, Honghu Zhu, Fangyi Dong, Hongming Zhu, Guoyu Meng, Junmin Li, Saijuan Chen, Zhu Chen, Hai Fang, Kankan Wang.
      Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.
    DOI:  https://doi.org/10.1038/s41467-024-45737-7
  24. Blood. 2024 Feb 16. pii: blood.2023021174. [Epub ahead of print]
    Blood and Guts: How the Intestinal Microbiome Shapes Hematopoiesis and Treatment of Hematologic Disease.
    Josaura Vanessa Fernandez Sanchez, Arushana Amir Maknojia, Katherine Y King.
      Over the past ten years there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady state blood production, affecting both hematopoietic stem and progenitor cells and differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis. Furthermore, the state of the microbiome is now recognized to affect outcomes from hematopoietic stem cell transplant, immunotherapy, and cellular therapies for hematologic malignancies. Here we review the mechanisms by which microbiota influence hematopoiesis in development and adulthood, as well as the avenues by which microbiota are thought to impact stem cell transplant engraftment, graft versus host disease, and efficacy of cell and immunotherapies. We highlight areas of future research that may lead to reduced adverse effects of antibiotic use and improved outcomes for patients with hematologic conditions.
    DOI:  https://doi.org/10.1182/blood.2023021174
  25. Br J Haematol. 2024 Jan 31.
    Promoter-centred chromatin interactions associated with EVI1 expression in EVI1+3q- myeloid leukaemia cells.
    Han Leng Ng, Mark E Robinson, Philippa C May, Andrew J Innes, Christina Hiemeyer, Niklas Feldhahn.
      EVI1 expression is associated with poor prognosis in myeloid leukaemia, which can result from Chr.3q alterations that juxtapose enhancers to induce EVI1 expression via long-range chromatin interactions. More often, however, EVI1 expression occurs unrelated to 3q alterations, and it remained unclear if, in these cases, EVI1 expression is similarly caused by aberrant enhancer activation. Here, we report that, in EVI1+3q- myeloid leukaemia cells, the EVI1 promoter interacts via long-range chromatin interactions with promoters of distally located, active genes, rather than with enhancer elements. Unlike in 3q+ cells, EVI1 expression and long-range interactions appear to not depend on CTCF/cohesin, though EVI1+3q- cells utilise an EVI1 promoter-proximal site to enhance its expression that is also involved in CTCF-mediated looping in 3q+ cells. Long-range interactions in 3q- cells connect EVI1 to promoters of multiple genes, whose transcription correlates with EVI1 in EVI1+3q- cell lines, suggesting a shared mechanism of transcriptional regulation. In line with this, CRISPR interference-induced silencing of two of these sites minimally, but consistently reduced EVI1 expression. Together, we provide novel evidence of features associated with EVI1 expression in 3q- leukaemia and consolidate the view that EVI1 in 3q- leukaemia is largely promoter-driven, potentially involving long-distance promoter clustering.
    Keywords:   EVI1 ; MECOM ; chromatin interaction; enhancer; oncogene regulation
    DOI:  https://doi.org/10.1111/bjh.19322
  26. Cell Rep. 2024 Feb 15. pii: S2211-1247(24)00122-0. [Epub ahead of print]43(2): 113794
    ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion.
    Barbara Bassani, Giorgia Simonetti, Valeria Cancila, Antonio Fiorino, Marilena Ciciarello, Annamaria Piva, Arman Mandegar Khorasani, Claudia Chiodoni, Daniele Lecis, Alessandro Gulino, Eugenio Fonzi, Laura Botti, Paola Portararo, Massimo Costanza, Marta Brambilla, Giorgia Colombo, Juerg Schwaller, Alexandar Tzankov, Maurilio Ponzoni, Fabio Ciceri, Niccolò Bolli, Antonio Curti, Claudio Tripodo, Mario P Colombo, Sabina Sangaletti.
      Acute myeloid leukemia (AML) progression is influenced by immune suppression induced by leukemia cells. ZEB1, a critical transcription factor in epithelial-to-mesenchymal transition, demonstrates immune regulatory functions in AML. Silencing ZEB1 in leukemic cells reduces engraftment and extramedullary disease in immune-competent mice, activating CD8 T lymphocytes and limiting Th17 cell expansion. ZEB1 in AML cells directly promotes Th17 cell development that, in turn, creates a self-sustaining loop and a pro-invasive phenotype, favoring transforming growth factor β (TGF-β), interleukin-23 (IL-23), and SOCS2 gene transcription. In bone marrow biopsies from AML patients, immunohistochemistry shows a direct correlation between ZEB1 and Th17. Also, the analysis of ZEB1 expression in larger datasets identifies two distinct AML groups, ZEB1high and ZEB1low, each with specific immunological and molecular traits. ZEB1high patients exhibit increased IL-17, SOCS2, and TGF-β pathways and a negative association with overall survival. This unveils ZEB1's dual role in AML, entwining pro-tumoral and immune regulatory capacities in AML blasts.
    Keywords:  CP: Immunology; Th17; immune suppression; leukemia; microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.113794
  27. Cancer. 2024 Feb 10.
    Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.
    Ashley Dinh, J Michael Savoy, Dimitrios P Kontoyiannis, Koichi Takahashi, Ghayas C Issa, Hagop M Kantarjian, Courtney D DiNardo, Caitlin R Rausch.
       BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown.
    METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole.
    RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily.
    CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.
    Keywords:  CYP450 inducer; QTc prolongation; drug-drug interactions; ivosidenib; posaconazole; venetoclax; voriconazole
    DOI:  https://doi.org/10.1002/cncr.35251
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