bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–11–05
35 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Criteria for diagnosis and molecular monitoring of NPM1-mutated AML.
  2. Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.
  3. Non-immunotherapy approaches for Relapsed or Refractory AML: an update for 2024.
  4. Erythroid differentiation enhances RNA mis-splicing in SF3B1-mutant myelodysplastic syndromes with ring sideroblasts.
  5. Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation.
  6. ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.
  7. Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.
  8. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
  9. Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation.
  10. SRCAP Mutations and Cellular Stressors Promote Clonal Hematopoiesis.
  11. The 'non-essential' amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
  12. ATP1A1/BCL2L1 predicts the response of myelomonocytic and monocytic acute myeloid leukemia to cardiac glycosides.
  13. Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.
  14. Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.
  15. AMPK activation induces immunogenic cell death in AML.
  16. Germline predisposition traits in allogeneic hematopoietic stem-cell transplantation for myelodysplastic syndromes: a survey-based study and position paper on behalf of the Chronic Malignancies Working Party of the EBMT.
  17. Regulation of lymphoid-myeloid lineage bias through Regnase-1/3-mediated control of Nfkbiz.
  18. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.
  19. Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials.
  20. ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms.
  21. Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target.
  22. How to discover the exceptional venetoclax responders in AML/MDS?
  23. Non-haematological grade 1 and 2 adverse events of frontline CPX-351 in patients with myelodysplastic syndromes.
  24. MEIS inhibitors reduce the viability of primary leukemia cells and Stem cells by inducing apoptosis.
  25. Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study.
  26. Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target.
  27. Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia.
  28. Impact of non-driver gene mutations on thrombo-haemorrhagic events in ET patients.
  29. Comprehensive characterization of patient-derived xenograft models of pediatric leukemia.
  30. Loss of GSK3β in hematopoietic stem cells results in normal hematopoiesis in mice.
  31. Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.
  32. Decitabine versus intensive chemotherapy induction for older patients with acute myeloid leukaemia: a futile but successful trial.
  33. Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing.
  34. In Utero Hematopoietic Cell Transplantation Leads to Sustained Engraftment in a Mouse Model of Fanconi Anemia.
  35. Slow cycling and durable Flt3+ progenitors contribute to hematopoiesis under native conditions.
  1. Blood Cancer Discov. 2023 Nov 02.
    Criteria for diagnosis and molecular monitoring of NPM1-mutated AML.
    Brunangelo Falini, Richard Dillon.
      NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML. NPM1-mutated AML is recognizable by molecular techniques and immunohistochemistry which, when combined, can solve difficult diagnostic problems (including identification of myeloid sarcoma and NPM1 mutations outside exon 12). According to the 2022 European LeukemiaNet (ELN), determining the mutational status of NPM1 (and FLT3) is a mandatory step for the genetic-based risk stratification of AML. Monitoring of MRD by RT-qPCR, combined with ELN risk-stratification, can guide therapeutic decisions at post-remission stage. Here, we review the criteria for appropriate diagnosis and molecular monitoring of NPM1-mutated AML.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0144
  2. Nat Cancer. 2023 Oct 30.
    Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.
    Claudia Bruedigam, Amy H Porter, Axia Song, Gerjanne Vroeg In de Wei, Thomas Stoll, Jasmin Straube, Leanne Cooper, Guidan Cheng, Vivian F S Kahl, Alexander P Sobinoff, Victoria Y Ling, Billy Michael Chelliah Jebaraj, Yashaswini Janardhanan, Rohit Haldar, Laura J Bray, Lars Bullinger, Florian H Heidel, Glen A Kennedy, Michelle M Hill, Hilda A Pickett, Omar Abdel-Wahab, Gunter Hartel, Steven W Lane.
      Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.
    DOI:  https://doi.org/10.1038/s43018-023-00653-5
  3. Acta Haematol. 2023 Oct 31.
    Non-immunotherapy approaches for Relapsed or Refractory AML: an update for 2024.
    Shira Buchrits, Ofir Wolach.
       BACKGROUND: Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML.
    SUMMARY: Inhibitors of FLT3 and IDH 1/2 are now FDA-approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed towards the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. Key-messages: Several new targeted therapies, immunologic and non-immunologic are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.
    DOI:  https://doi.org/10.1159/000534897
  4. Cancer Res. 2023 Nov 03.
    Erythroid differentiation enhances RNA mis-splicing in SF3B1-mutant myelodysplastic syndromes with ring sideroblasts.
    Pedro L Moura, Teresa Mortera Blanco, Isabel J Hofman, Gabriele Todisco, Warren W Kretzschmar, Ann-Charlotte Björklund, Maria Creignou, Michael Hagemann-Jensen, Christoph Ziegenhain, David Cabrerizo Granados, Indira Barbosa, Gunilla Walldin, Monika Jansson, Neil Ashley, Adam J Mead, Vanessa Lundin, Marios Dimitriou, Tetsuichi Yoshizato, Petter S Woll, Seishi Ogawa, Rickard Sandberg, Sten-Eirik W Jacobsen, Eva Hellström-Lindberg.
      Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly develop from hematopoietic stem cells (HSC) bearing mutations in the splicing factor SF3B1 (SF3B1mt). Direct studies into MDS-RS pathobiology have been limited by a lack of model systems that fully recapitulate erythroid biology and RS development and the inability to isolate viable human RS. Here, we combined successful direct RS isolation from patient samples, high-throughput multiomics analysis of cells encompassing the SF3B1mt stem-erythroid continuum, and functional assays to investigate the impact of SF3B1mt on erythropoiesis and RS accumulation. The isolated RS differentiated, egressed into the blood, escaped traditional nonsense-mediated decay (NMD) mechanisms, and leveraged stress-survival pathways that hinder wild-type hematopoiesis through pathogenic GDF15 overexpression. Importantly, RS constituted a contaminant of magnetically-enriched CD34+ cells, skewing bulk transcriptomic data. Mis-splicing in SF3B1mt cells was intensified by erythroid differentiation through accelerated RNA splicing and decreased NMD activity, and SF3B1mt led to truncations in several MDS-implicated genes. Finally, RNA mis-splicing induced an uncoupling of RNA and protein expression, leading to critical abnormalities in proapoptotic p53 pathway genes. Overall, this characterization of erythropoiesis in SF3B1mt RS provides a resource for studying MDS-RS and uncovers insights into the unexpectedly active biology of the "dead-end" RS.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3038
  5. Leukemia. 2023 Nov 02.
    Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation.
    Jani Huuhtanen, Shady Adnan-Awad, Jason Theodoropoulos, Sofia Forstén, Rebecca Warfvinge, Olli Dufva, Jonas Bouhlal, Parashar Dhapola, Hanna Duàn, Essi Laajala, Tiina Kasanen, Jay Klievink, Mette Ilander, Taina Jaatinen, Ulla Olsson-Strömberg, Henrik Hjorth-Hansen, Andreas Burchert, Göran Karlsson, Anna Kreutzman, Harri Lähdesmäki, Satu Mustjoki.
      Immunological control of residual leukemia cells is thought to occur in patients with chronic myeloid leukemia (CML) that maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. To study this, we analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced samples (scRNA+TCRαβ-seq) from patients with CML (n = 13, N = 25), other cancers (n = 28), and healthy (n = 7). The high number and active phenotype of natural killer (NK) cells in CML separated them from healthy and other cancers. Most NK cells in CML belonged to the active CD56dim cluster with high expression of GZMA/B, PRF1, CCL3/4, and IFNG, with interactions with leukemic cells via inhibitory LGALS9-TIM3 and PVR-TIGIT interactions. Accordingly, upregulation of LGALS9 was observed in CML target cells and TIM3 in NK cells when co-cultured together. Additionally, we created a classifier to identify TCRs targeting leukemia-associated antigen PR1 and quantified anti-PR1 T cells in 90 CML and 786 healthy TCRβ-sequenced samples. Anti-PR1 T cells were more prevalent in CML, enriched in bone marrow samples, and enriched in the mature, cytotoxic CD8 + TEMRA cluster, especially in a patient maintaining TFR. Our results highlight the role of NK cells and anti-PR1 T cells in anti-leukemic immune responses in CML.
    DOI:  https://doi.org/10.1038/s41375-023-02074-w
  6. Haematologica. 2023 Nov 02.
    ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.
    Vladimir Riabov, Qingyu Xu, Nanni Schmitt, Alexander Streuer, Guo Ge, Lyndsey Bolanos, Mark Wunderlich, Johann-Christoph Jann, Alina Wein, Eva Altrock, Marie Demmerle, Sanjay Mukherjee, Abdullah Mahmood Ali, Felicitas Rapp, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Melda Göl, Ahmed Jawhar, Ali Darwich, Patrick Wuchter, Christel Weiss, Azra Raza, Jason M Foulks, Daniel T Starczynowski, Feng-Chun Yang, Georgia Metzgeroth, Laurenz Steiner, Mohamad Jawhar, Wolf-Karsten Hofmann, Daniel Nowak.
      Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.
    DOI:  https://doi.org/10.3324/haematol.2023.282921
  7. J Clin Invest. 2023 Nov 02. pii: e163964. [Epub ahead of print]
    Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.
    Guo Ge, Peng Zhang, Pinpin Sui, Shi Chen, Hui Yang, Ying Guo, Ivan P Rubalcava, Asra Noor, Caroline R Delma, Joel Agosto-Peña, Hui Geng, Edward A Medina, Ying Liang, Stephen D Nimer, Ruben Mesa, Omar Abdel-Wahab, Mingjiang Xu, Feng-Chun Yang.
      ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb Repressive Complex 2 (PRC2) to specific gene loci to repress transcription through tri-methylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered up-regulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1 mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.
    Keywords:  Hematology; Hematopoietic stem cells; Leukemias; Mouse models
    DOI:  https://doi.org/10.1172/JCI163964
  8. Lancet Haematol. 2023 Nov;pii: S2352-3026(23)00273-9. [Epub ahead of print]10(11): e879-e889
    10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
    EORTC Leukemia Group, GIMEMA, and German MDS Study Group
       BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
    METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
    FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
    INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
    FUNDING: Janssen Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00273-9
  9. Nat Commun. 2023 Oct 30. 14(1): 6907
    Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation.
    Dongmei Wang, Tao Sun, Yuan Xia, Zhe Zhao, Xue Sheng, Shuying Li, Yuechan Ma, Mingying Li, Xiuhua Su, Fan Zhang, Peng Li, Daoxin Ma, Jingjing Ye, Fei Lu, Chunyan Ji.
      CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
    DOI:  https://doi.org/10.1038/s41467-023-42650-3
  10. Cancer Discov. 2023 Nov 03. OF1
    SRCAP Mutations and Cellular Stressors Promote Clonal Hematopoiesis.
      SRCAP mutations promote clonal expansion of hematopoietic stem cells (HSC) in response to cellular stress.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-175
  11. Blood Adv. 2023 Oct 31. pii: bloodadvances.2023010786. [Epub ahead of print]
    The 'non-essential' amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
    Alan Cunningham, Lieve Oudejans, Marjan Geugien, Diego A Pereira-Martins, Albertus Tj Wierenga, Ayşegül Erdem, Dominique Sternadt, Gerwin A Huls, Jan Jacob Schuringa.
      Cysteine is a non-essential amino acid required for protein synthesis, the generation of the anti-oxidant glutathione and for synthesizing the non-proteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/Cas9-mediated knockout of cystathionine-γ-Lysase (CTH), the cystathionine to cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, while perhaps nutritionally non-essential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels and cell death was induced predominantly as a consequence of glutathione deprivation. NADPH oxidase (NOX) inhibition strongly rescued viability following cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of GPX4, which functions to reduce lipid peroxides, was also highly toxic and we therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with Auranofin also impaired cell viability, whereby we find that in particular OXPHOS-driven AML subtypes are highly dependent on thioredoxin-mediated protection against ferroptosis. While inhibition of the cystine importer xCT with Sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either Sulfasalazine or anti-oxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further pre-clinical testing.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010786
  12. Leukemia. 2023 Oct 30.
    ATP1A1/BCL2L1 predicts the response of myelomonocytic and monocytic acute myeloid leukemia to cardiac glycosides.
    Claudia Cerella, Sruthi Reddy Gajulapalli, Anne Lorant, Deborah Gerard, Florian Muller, Yejin Lee, Kyung Rok Kim, Byung Woo Han, Christo Christov, Christian Récher, Jean-Emmanuel Sarry, Mario Dicato, Marc Diederich.
      Myelomonocytic and monocytic acute myeloid leukemia (AML) subtypes are intrinsically resistant to venetoclax-based regimens. Identifying targetable vulnerabilities would limit resistance and relapse. We previously documented the synergism of venetoclax and cardiac glycoside (CG) combination in AML. Despite preclinical evidence, the repurposing of cardiac glycosides (CGs) in cancer therapy remained unsuccessful due to a lack of predictive biomarkers. We report that the ex vivo response of AML patient blasts and the in vitro sensitivity of established cell lines to the hemi-synthetic CG UNBS1450 correlates with the ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1)/BCL2 like 1 (BCL2L1) expression ratio. Publicly available AML datasets identify myelomonocytic/monocytic differentiation as the most robust prognostic feature, along with core-binding factor subunit beta (CBFB), lysine methyltransferase 2A (KMT2A) rearrangements, and missense Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Mechanistically, BCL2L1 protects from cell death commitment induced by the CG-mediated stepwise triggering of ionic perturbation, protein synthesis inhibition, and MCL1 downregulation. In vivo, CGs showed an overall tolerable profile while impacting tumor growth with an effect ranging from tumor growth inhibition to regression. These findings suggest a predictive marker for CG repurposing in specific AML subtypes.
    DOI:  https://doi.org/10.1038/s41375-023-02076-8
  13. Leuk Lymphoma. 2023 Nov 03. 1-10
    Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.
    Steven M Johnson, James Haberberger, Jonathan Galeotti, Lori Ramkissoon, Catherine C Coombs, Daniel R Richardson, Matthew C Foster, Daniel Duncan, Nathan D Montgomery, Naomi L Ferguson, Joshua F Zeidner.
      A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.
    Keywords:  Myeloid leukemias and dysplasias; molecular genetics; myeloproliferative disorders; neoplasia
    DOI:  https://doi.org/10.1080/10428194.2023.2277672
  14. Blood Adv. 2023 Oct 30. pii: bloodadvances.2023010943. [Epub ahead of print]
    Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.
    Jessica K Altman, Tsila Zuckerman, Jamie Koprivnikar, James McCloskey, Vamsi Kota, Michael Keng, Olga Frankfurt, Yasmin Abaza, Dale Bixby, Ashkan Emadi, Micah Burch, Bhavana Bhatnagar, Selina M Luger, Mary-Elizabeth M Percival, Ofir Wolach, Michael Craig, Chezi Ganzel, Gail J Roboz, Itai Levi, Anna Gourevitch, Liat Flaishon, Shoshi Tessler, Chen Blomberg, Stela Gengrinovitch, Ruth Ben Yakar, Jacob M Rowe.
      High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity precluding its use in older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study, in patients with AML unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2/d (equimolar to 3 g/m2/d cytarabine) for 6 doses per treatment courses. The median age was 75 years; 60.6% had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome and 10.6% therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents and patients with TP53-mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range 6 to 15.9) and not reached among responders. Hematologic recovery was observed in all responding patients by day 26 with no prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. Aspacytarabine appears to be an effective regimen, with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010943
  15. Blood Adv. 2023 Oct 30. pii: bloodadvances.2022009444. [Epub ahead of print]
    AMPK activation induces immunogenic cell death in AML.
    Johanna Mondesir, Margherita Ghisi, Laura Poillet, Robert A Bossong, Oliver Kepp, Guido Kroemer, Jean-Emmanuel Sarry, Jérôme Tamburini, Andrew A Lane.
      Survival of patients with acute myeloid leukemia (AML) can be improved by allogenic hematopoietic stem cell transplantation (alloHSCT) due to the anti-leukemic activity of T- and NK-cells from the donor. However, the use of alloHSCT is limited by donor availability, recipient age, and potential severe side effects. Similarly, the efficacy of immunotherapies directing autologous T-cells against tumor cells, including T-cell recruiting antibodies, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors is limited in AML due to multiple mechanisms of leukemia immune escape. This has prompted a search for novel immunostimulatory approaches. Here, we show that activation of AMP-activated protein kinase (AMPK), a master regulator of cellular energy balance, by the small molecule GSK621 induces calreticulin (CALR) membrane exposure in murine and human AML cells. When CALR is exposed on the cell surface, it serves as a damage-associated molecular pattern (DAMP) that stimulates immune responses. We found that GSK621-treated murine leukemia cells promote the activation and maturation of bone marrow-derived dendritic cells. Moreover, vaccination with GSK621-treated leukemia cells had a protective effect in syngeneic immunocompetent recipients bearing transplanted AMLs. This effect was lost in recipients depleted of CD4/CD8 T cells. Together, these results demonstrate that AMPK activation by GSK621 elicits traits of immunogenic cell death and promotes a robust immune response against leukemia. Pharmacologic AMPK activation thus represents a new potential target for improving the activity of immunotherapy in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009444
  16. Lancet Haematol. 2023 Oct 25. pii: S2352-3026(23)00265-X. [Epub ahead of print]
    Germline predisposition traits in allogeneic hematopoietic stem-cell transplantation for myelodysplastic syndromes: a survey-based study and position paper on behalf of the Chronic Malignancies Working Party of the EBMT.
    Carmelo Gurnari, Marie Robin, Lucy A Godley, Joanna Drozd-Sokołowska, Marcin W Włodarski, Kavita Raj, Francesco Onida, Nina Worel, Fabio Ciceri, Selim Carbacioglu, Michelle Kenyon, Mahmoud Aljurf, Carmem Bonfim, Hideki Makishima, Charlotte Niemeyer, Pierre Fenaux, Armin Zebisch, Nada Hamad, Yves Chalandon, Eva Hellström-Lindberg, Maria Teresa Voso, Cristina Mecucci, Fernando Barroso Duarte, Marie Sebert, Flore Sicre de Fontbrune, Jean Soulier, Akiko Shimamura, R Coleman Lindsley, Jarosław P Maciejewski, Rodrigo T Calado, Ibrahim Yakoub-Agha, Donal P McLornan.
      The recent application of whole exome or whole genome sequencing unveiled a plethora of germline variants predisposing to myeloid disorders, particularly myelodysplastic neoplasms. The presence of such variants in patients with myelodysplastic syndromes has important clinical repercussions for haematopoietic stem-cell transplantation, from donor selection and conditioning regimen to graft-versus-host disease prophylaxis and genetic counselling for relatives. No international guidelines exist to harmonise management approaches to this particular clinical scenario. Moreover, the application of germline testing, and how this informs clinical decisions, differs according to the expertise of individual clinical practices and according to different countries, health-care systems, and legislations. Leveraging the global span of the European Society for Blood and Marrow Transplantation (EBMT) network, we took a snapshot of the current European situation on these matters by disseminating an electronic survey to EBMT centres experienced in myelodysplastic syndromes transplantation. An international group of haematologists, transplantation physicians, paediatricians, nurses, and experts in molecular biology and constitutional genetics with experience in myelodysplastic syndromes contributed to this Position Paper. The panel met during multiple online meetings to discuss the results of the EBMT survey and to establish suggested harmonised guidelines for such clinical situations, which are presented here.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00265-X
  17. Blood. 2023 Nov 03. pii: blood.2023020903. [Epub ahead of print]
    Regulation of lymphoid-myeloid lineage bias through Regnase-1/3-mediated control of Nfkbiz.
    Takuya Uehata, Shinnosuke Yamada, Daisuke Ori, Alexis Vandenbon, Amir Giladi, Adam Jelinski, Yasuhiro Murakawa, Hitomi Watanabe, Kazuhiro Takeuchi, Kazunori Toratani, Takashi Mino, Hisanori Kiryu, Daron M Standley, Tohru Tsujimura, Tomokatsu Ikawa, Gen Kondoh, Markus Landthaler, Hiroshi Kawamoto, Hans-Reimer Rodewald, Ido Amit, Ryo Yamamoto, Masaki Miyazaki, Osamu Takeuchi.
      Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Reg1; Zc3h12a) and Regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs. Loss of Reg1 and Reg3 resulted in severe impairment of lymphopoiesis and a mild increase in myelopoiesis in the BM. single cell RNA sequencing analysis (scRNA-seq) revealed that Reg1 and Reg3 regulate lineage directions in HSPCs via the control of a set of myeloid-related genes. Reg1- and Reg3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Reg1 and Reg3 control the epigenetic landscape on myeloid-related gene loci in early-stage HSPCs via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Reg1- and Reg3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Reg1/Reg3-Nfkbiz axis governs HSPC lineage biases, ultimately dictating the fate of lymphoid versus myeloid differentiation.
    DOI:  https://doi.org/10.1182/blood.2023020903
  18. Lancet Haematol. 2023 Nov;pii: S2352-3026(23)00207-7. [Epub ahead of print]10(11): e902-e912
    Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.
    Thomas Pabst, Cristina Papayannidis, Fatih Demirkan, Vadim Doronin, Laura M Fogliatto, Christina Guttke, Emmanuel Gyan, Nada Hamad, Pilar Herrera, Anna Hultberg, Julie Jacobs, Amy J Johnson, Angélique Langlois, Xuewen Ma, Giovanni Martinelli, Montserrat Arnan, Rouven Müller, Kerri Nottage, Yishai Ofran, Muhit Özcan, Olga Samoilova, Jaszianne A Tolbert, Géralyn C Trudel, Liang Xiu, Norbert Vey, Andrew H Wei.
       BACKGROUND: Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy.
    METHODS: In this randomised, phase 2, open-label, dose-optimisation study we enrolled adult patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy, and with Eastern Cooperative Oncology Group scores of 0-2, from 40 hospitals and centres across seven countries. In part one of the trial, participants were randomly allocated 1:1 to 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17, combined with subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles. The primary efficacy outcome was the rate of complete remission in the intention-to-treat group. The two dose cohorts were evaluated independently without between-cohort statistical comparison. Safety analyses were performed in all patients who received one dose of study drug. Part two of the trial was planned to be a single-arm expansion to evaluate cusatuzumab plus azacitidine at the cusatuzumab dose level selected in part one (primary hypothesis ≥35% rate of complete remission vs null hypothesis of 20%); however, changes in the acute myeloid leukaemia treatment landscape during this trial made it unlikely that enrolment to part two of the study would be clinically feasible, so the study stopped at the end of part one. The trial was registered at ClinicalTrials.gov, NCT04023526.
    FINDINGS: 103 patients were enrolled between Aug 30, 2019, and Feb 25, 2020, and randomly assigned to either cusatuzumab 10 mg/kg (n=51) or 20 mg/kg (n=52). Median follow-up was 7·2 months (IQR 10·7 months). 57 of 103 (55%) patients were male and 46 (45%) patients were female, 78 (76%) were White, one (1%) was Asian, and 24 (23%) did not report their race. In the 10 mg/kg group, complete remission rate was 12% (six of 51 patients; 95% CI 6-23) and in the 20 mg/kg group was 27% (14 of 52; 17-40). Grade 3 or worse treatment-emergent adverse events (TEAEs) were similar between the cusatuzumab 10 mg/kg (n=51) and 20 mg/kg (n=51) cohorts and included thrombocytopenia (24 patients [47%] vs 29 [57%]), anaemia (24 [47%] vs 17 [33%]), and neutropenia (20 [39%] in both cohorts). Serious TEAEs were also similar in the two cohorts (44 [86%] vs 40 [78%]). Treatment-related TEAEs leading to death were reported in both groups (three patients [6%] in the 10 mg/kg group vs one patient [2%] in the 20 mg/kg group); the reported causes of death were pneumonia (n=2) and septic shock (n=2).
    INTERPRETATION: Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887).
    FUNDING: Janssen Research & Development and argenx.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00207-7
  19. Hemasphere. 2023 Nov;7(11): e963
    Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials.
    Jean-Jacques Kiladjian, Alessandro M Vannucchi, Aaron T Gerds, Vikas Gupta, Srdan Verstovsek, Miklos Egyed, Uwe Platzbecker, Jiří Mayer, Sebastian Grosicki, Árpád Illés, Tomasz Woźny, Stephen T Oh, Donal McLornan, Ilya Kirgner, Sung-Soo Yoon, Claire N Harrison, Barbara Klencke, Mei Huang, Jun Kawashima, Ruben Mesa.
      The oral activin A receptor type I, Janus kinase 1 (JAK1), and JAK2 inhibitor momelotinib demonstrated symptom, spleen, and anemia benefits in intermediate- and high-risk myelofibrosis (MF). Post hoc analyses herein evaluated the efficacy and safety of momelotinib in patients with MF and thrombocytopenia (platelet counts <100 × 109/L) from randomized phase 3 studies: MOMENTUM (momelotinib versus danazol; JAK inhibitor experienced); SIMPLIFY-1 (momelotinib versus ruxolitinib; JAK inhibitor naïve); and SIMPLIFY-2 (momelotinib versus best available therapy; JAK inhibitor experienced); these studies were not statistically powered to assess differences in thrombocytopenic subgroups, and these analyses are descriptive. The treatment effect of momelotinib versus ruxolitinib on week 24 response rates (spleen volume reduction ≥35%/Total Symptom Score reduction ≥50%/transfusion independence) was numerically comparable or better in thrombocytopenic patients versus the overall JAK inhibitor naive population; rates were preserved with momelotinib in thrombocytopenic patients but attenuated with ruxolitinib (momelotinib: 27%/28%/67% overall versus 39%/35%/61% in thrombocytopenic group; ruxolitinib: 29%/42%/49% overall versus 0%/22%/39% in thrombocytopenic group, respectively). In contrast to ruxolitinib, momelotinib maintained high dose intensity throughout the treatment. In the JAK inhibitor experienced population, thrombocytopenic patients had the following: (1) numerically higher symptom and transfusion independence response rates with momelotinib than in control arms; and (2) preserved spleen, symptom, and transfusion independence response rates with momelotinib relative to the overall study populations. The safety profile of momelotinib in thrombocytopenic patients was also consistent with the overall study population. In summary, momelotinib represents a safe and effective treatment option for patients with MF and moderate-to-severe thrombocytopenia.
    DOI:  https://doi.org/10.1097/HS9.0000000000000963
  20. Leukemia. 2023 Nov 03.
    ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms.
    Hassan Awada, Manasa Bhatta, Han Yu, Wenyan Ji, Surui Hou, Tara Cronin, Sheeba Ba Aqeel, Arya Mariam Roy, Muhammad Salman Faisal, Peter Kouides, John Mascarenhas, Elizabeth A Griffiths, Amro Elshoury.
      
    DOI:  https://doi.org/10.1038/s41375-023-02069-7
  21. Leukemia. 2023 Nov 02.
    Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target.
    Yu-Hung Wang, Chien-Chin Lin, Kristian Gurashi, Bettina Wingelhofer, Fabio M R Amaral, Chi-Yuan Yao, Hsin Ting Hsieh, Ming Chih Liu, Hsin-An Hou, Wen-Chien Chou, Kiran Batta, Daniel H Wiseman, Hwei-Fang Tien.
      
    DOI:  https://doi.org/10.1038/s41375-023-02044-2
  22. Br J Haematol. 2023 Nov 02.
    How to discover the exceptional venetoclax responders in AML/MDS?
    Bjørn Tore Gjertsen.
      
    Keywords:   DDX41 ; AML; MDS; exceptional responders; hypomethylating agent; real-world analysis; venetoclax
    DOI:  https://doi.org/10.1111/bjh.19165
  23. Lancet Haematol. 2023 Nov;pii: S2352-3026(23)00272-7. [Epub ahead of print]10(11): e872
    Non-haematological grade 1 and 2 adverse events of frontline CPX-351 in patients with myelodysplastic syndromes.
    Koji Sasaki.
      
    DOI:  https://doi.org/10.1016/S2352-3026(23)00272-7
  24. Leuk Lymphoma. 2023 Oct 30. 1-12
    MEIS inhibitors reduce the viability of primary leukemia cells and Stem cells by inducing apoptosis.
    Neslihan Meriç, Esra Albayrak, Zafer Gülbaş, Fatih Kocabaş.
      Leukemia stem cells (LSCs) exhibit self-renewal, resistance to standard treatments, and involvement in leukemia relapse. Higher Myeloid Ecotropic Integration Site-1 (MEIS1) expression in leukemic blast samples has been linked to resistance to conventional treatment. We studied the MEIS1 and associated factors in relapsed LSCs and assessed the effect of recently developed MEIS inhibitors (MEISi). Meis1 gene expression was found to be higher in patients with leukemia and relapsed samples. The majority of CD123+ and CD34+ LSCs demonstrated higher MEIS1/2/3 content. Depending on the patient chemotherapy regimen, Meis1 expression increased in relapsed samples. Although there are increased Meis2, Meis3, Hoxa9, Pbx1, or CD34 expressions in the relapsed patients, they are not correlated with Meis1 content in every patient or regimen. MEISi has reduced MEIS1 transcriptional activity and LSC cell survival by apoptosis. Pharmacological targeting with MEISi in LSCs could have a potential effect in limiting leukemia relapse and chemotherapeutic resistance.
    Keywords:  Acute leukemia; LSCs; MEIS inhibitor; Meis1
    DOI:  https://doi.org/10.1080/10428194.2023.2275532
  25. Hemasphere. 2023 Nov;7(11): e966
    Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study.
    Ruben A Mesa, Claire Harrison, Jeanne M Palmer, Vikas Gupta, Donal P McLornan, Mary Frances McMullin, Jean-Jacques Kiladjian, Lynda Foltz, Uwe Platzbecker, Maria Laura Fox, Adam J Mead, David M Ross, Stephen T Oh, Andrew Charles Perkins, Michael F Leahy, Jun Kawashima, Sunhee Ro, Rafe Donahue, Boris Gorsh, Samineh Deheshi, Srdan Verstovsek.
      Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.
    DOI:  https://doi.org/10.1097/HS9.0000000000000966
  26. Nat Cancer. 2023 Oct 30.
    Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target.
    Kamal Mandal, Gianina Wicaksono, Clinton Yu, Jarrett J Adams, Michael R Hoopmann, William C Temple, Adila Izgutdina, Bonell Patiño Escobar, Maryna Gorelik, Christian H Ihling, Matthew A Nix, Akul Naik, William H Xie, Juwita Hübner, Lisa A Rollins, Sandy M Reid, Emilio Ramos, Corynn Kasap, Veronica Steri, Juan Antonio Camara Serrano, Fernando Salangsang, Paul Phojanakong, Melanie McMillan, Victor Gavallos, Andrew D Leavitt, Aaron C Logan, Cliona M Rooney, Justin Eyquem, Andrea Sinz, Benjamin J Huang, Elliot Stieglitz, Catherine C Smith, Robert L Moritz, Sachdev S Sidhu, Lan Huang, Arun P Wiita.
      Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.
    DOI:  https://doi.org/10.1038/s43018-023-00652-6
  27. Blood. 2023 Nov 03. pii: blood.2023020857. [Epub ahead of print]
    Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia.
    Kazunari Aoki, Mizuki Hyuga, Yusuke Tarumoto, Gohei Nishibuchi, Atsushi Ueda, Yotaro Ochi, Seiichi Sugino, Takashi Mikami, Hirokazu Kobushi, Itaru Kato, Koshi Akahane, Takeshi Inukai, Akifumi Takaori-Kondo, Junko Takita, Seishi Ogawa, Kosuke Yusa.
      Acute leukemia cells require bone marrow microenvironments, termed niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose non-fermenting chromatin remodeling complex, regulates migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.
    DOI:  https://doi.org/10.1182/blood.2023020857
  28. Br J Haematol. 2023 Nov 02.
    Impact of non-driver gene mutations on thrombo-haemorrhagic events in ET patients.
    Chiho Furuya, Soji Morishita, Yoshinori Hashimoto, Tadaaki Inano, Tomonori Ochiai, Shuichi Shirane, Yoko Edahiro, Marito Araki, Miki Ando, Norio Komatsu.
      Risk-adapted therapy is recommended to prevent major clinical complications, such as thrombo-haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non-driver gene mutations and thrombo-haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis-free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F-mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage-free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A-mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non-driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches.
    Keywords:  ASXL1 mutation; DNMT3A mutation; essential thrombocythaemia; haemorrhage; thrombosis
    DOI:  https://doi.org/10.1111/bjh.19177
  29. iScience. 2023 Nov 17. 26(11): 108171
    Comprehensive characterization of patient-derived xenograft models of pediatric leukemia.
    Anna Rogojina, Laura J Klesse, Erin Butler, Jiwoong Kim, He Zhang, Xue Xiao, Lei Guo, Qinbo Zhou, Taylor Hartshorne, Dawn Garcia, Korri Weldon, Trevor Holland, Abhik Bandyopadhyay, Luz Perez Prado, Shidan Wang, Donghan M Yang, Anne-Marie Langevan, Yi Zou, Allison C Grimes, Chatchawin Assanasen, Vinod Gidvani-Diaz, Siyuan Zheng, Zhao Lai, Yidong Chen, Yang Xie, Gail E Tomlinson, Stephen X Skapek, Raushan T Kurmasheva, Peter J Houghton, Lin Xu.
      Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%). With a new algorithm to remove mouse contamination in multi-omics datasets including methylation data, we found PDX models faithfully reflected somatic mutations, copy-number alterations, RNA expression, gene fusions, whole-genome methylation patterns, and immunophenotypes found in primary tumor (PT) samples in the first 50 reported here. This cohort of characterized PDX childhood leukemias represents a valuable resource in that germline DNA sequencing has allowed the unambiguous determination of somatic mutations in both PT and PDX.
    Keywords:  Cancer; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108171
  30. Blood Adv. 2023 Oct 19. pii: bloodadvances.2022008094. [Epub ahead of print]
    Loss of GSK3β in hematopoietic stem cells results in normal hematopoiesis in mice.
    Grace Lee, Jude Sundar Franklin, Kalpana Gupta, Ruifu Liu, Lan Zhou, Christopher Ryder, Lukasz Sobieraj, Luke Molitor, Olubukola Abiona, Howard Meyerson, Indrani Das, Zachary Jackson, David N Wald.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022008094
  31. JCI Insight. 2023 Oct 31. pii: e172851. [Epub ahead of print]
    Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.
    Ying Ting Sit, Kaoru Takasaki, Hyun Hyung An, Yan Xiao, Christian Hurtz, Peter Gearhart, Zhe Zhang, Paul Gadue, Deborah French, Stella T Chou.
      Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that DYRK1A and GATA1 may synergistically restrain megakaryocyte proliferation in Trisomy 21 and that DYRK1A inhibition may not be a therapeutic option for GATA1s-associated leukemias.
    Keywords:  Hematology; Leukemias; iPS cells
    DOI:  https://doi.org/10.1172/jci.insight.172851
  32. Lancet Haematol. 2023 Nov;pii: S2352-3026(23)00308-3. [Epub ahead of print]10(11): e866-e867
    Decitabine versus intensive chemotherapy induction for older patients with acute myeloid leukaemia: a futile but successful trial.
    Pau Montesinos, Claudia Sossa-Melo.
      
    DOI:  https://doi.org/10.1016/S2352-3026(23)00308-3
  33. Nat Commun. 2023 10 28. 14(1): 6895
    Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing.
    Ryan N Ptashkin, Mark D Ewalt, Gowtham Jayakumaran, Iwona Kiecka, Anita S Bowman, JinJuan Yao, Jacklyn Casanova, Yun-Te David Lin, Kseniya Petrova-Drus, Abhinita S Mohanty, Ruben Bacares, Jamal Benhamida, Satshil Rana, Anna Razumova, Chad Vanderbilt, Anoop Balakrishnan Rema, Ivelise Rijo, Julie Son-Garcia, Ino de Bruijn, Menglei Zhu, Sean Lachhander, Wei Wang, Mohammad S Haque, Venkatraman E Seshan, Jiajing Wang, Ying Liu, Khedoudja Nafa, Laetitia Borsu, Yanming Zhang, Umut Aypar, Sarah P Suehnholz, Debyani Chakravarty, Jae H Park, Omar Abdel-Wahab, Anthony R Mato, Wenbin Xiao, Mikhail Roshal, Mariko Yabe, Connie Lee Batlevi, Sergio Giralt, Gilles Salles, Raajit Rampal, Martin Tallman, Eytan M Stein, Anas Younes, Ross L Levine, Miguel-Angel Perales, Marcel R M van den Brink, Ahmet Dogan, Marc Ladanyi, Michael F Berger, A Rose Brannon, Ryma Benayed, Ahmet Zehir, Maria E Arcila.
      Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
    DOI:  https://doi.org/10.1038/s41467-023-42585-9
  34. Blood Adv. 2023 Oct 31. pii: bloodadvances.2023010354. [Epub ahead of print]
    In Utero Hematopoietic Cell Transplantation Leads to Sustained Engraftment in a Mouse Model of Fanconi Anemia.
    Apeksha Dave, Suying Liu, John Samuel Riley, Sourav K Bose, Valerie L Luks, Cara L Berkowitz, Pallavi Menon, Seul K Jung, Haiying Li, Peter Kurre, William H Peranteau.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023010354
  35. J Exp Med. 2024 Jan 01. pii: e20231035. [Epub ahead of print]221(1):
    Slow cycling and durable Flt3+ progenitors contribute to hematopoiesis under native conditions.
    Michael Solomon, Baobao Song, Vinothini Govindarajah, Samantha Good, Ashok Arasu, E Broderick Hinton, Kairavee Thakkar, James Bartram, Marie-Dominique Filippi, Jose A Cancelas, Nathan Salomonis, H Leighton Grimes, Damien Reynaud.
      The dynamics of the hematopoietic flux responsible for blood cell production in native conditions remains a matter of debate. Using CITE-seq analyses, we uncovered a distinct progenitor population that displays a cell cycle gene signature similar to the one found in quiescent hematopoietic stem cells. We further determined that the CD62L marker can be used to phenotypically enrich this population in the Flt3+ multipotent progenitor (MPP4) compartment. Functional in vitro and in vivo analyses validated the heterogeneity of the MPP4 compartment and established the quiescent/slow-cycling properties of the CD62L- MPP4 cells. Furthermore, studies under native conditions revealed a novel hierarchical organization of the MPP compartments in which quiescent/slow-cycling MPP4 cells sustain a prolonged hematopoietic activity at steady-state while giving rise to other lineage-biased MPP populations. Altogether, our data characterize a durable and productive quiescent/slow-cycling hematopoietic intermediary within the MPP4 compartment and highlight early paths of progenitor differentiation during unperturbed hematopoiesis.
    DOI:  https://doi.org/10.1084/jem.20231035
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