bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–02–25
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.
  2. An arms-race against resistance: leukemic stem cells and lineage plasticity.
  3. Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML.
  4. CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression.
  5. Venetoclax with decitabine or azacitidine in relapsed or refractory acute myeloid leukemia.
  6. Risk models in myelofibrosis-the past, present, and future.
  7. Venetoclax in the treatment of acute myeloid leukemia: Beyond VIALE-A.
  8. Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
  9. Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT.
  10. Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation.
  11. Infrequent Presentations of Chronic NPM1-Mutated Myeloid Neoplasms: Clinicopathological Features of Eight Cases from a Single Institution and Review of the Literature.
  12. Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients - A clinical trial to registry data comparison.
  13. A new SAGA for AML: targeting SGF29 in AML.
  14. Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations.
  15. Pretransplantation predictors of survival in nonremission acute myeloid leukemia treated with haploidentical transplantation using steroid-based GVHD prophylaxis.
  16. Germline CHEK2 mutations in patients with myeloid neoplasms.
  17. Single-Cell CD4 and CD8 T Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy.
  18. Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).
  19. Clinical impact of genetic alterations including germline DDX41 mutations in MDS/low-blast count AML patients treated with azacitidine-based regimens.
  20. Deregulation of the p19/CDK4/CDK6 axis in Jak2V617F megakaryocytes accelerates the development of myelofibrosis.
  21. The evolution of preclinical models for myelodysplastic neoplasms.
  22. Mechanisms of action and resistance in histone methylation-targeted therapy.
  23. Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial.
  24. Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.
  25. An immunogenetic basis for lung cancer risk.
  26. Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease.
  27. Generation of complex bone marrow organoids from human induced pluripotent stem cells.
  28. Reconstructing phylogenetic trees from genome-wide somatic mutations in clonal samples.
  29. Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Strategies to Optimize Success and New Directions.
  30. Ectopic expression of transcription factor ONECUT3 drives complex karyotype in Myelodysplastic Syndromes.
  31. Myelofibrosis: Current unmet needs, emerging treatments, and future perspectives.
  32. Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive post-remission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia.
  33. Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
  34. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
  35. NPM1-mutated myeloid neoplasm with low percentage of blasts.
  36. Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery.
  1. Leukemia. 2024 Feb 20.
    Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.
    Shai Shimony, Jan Philipp Bewersdorf, Rory M Shallis, Yiwen Liu, Eva J Schaefer, Amer M Zeidan, Aaron D Goldberg, Eytan M Stein, Guido Marcucci, R Coleman Lindsley, Evan C Chen, Jorge Ramos Perez, Anthony Stein, Daniel J DeAngelo, Donna S Neuberg, Richard M Stone, Brian Ball, Maximilian Stahl.
      Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.
    DOI:  https://doi.org/10.1038/s41375-024-02175-0
  2. Mol Oncol. 2024 Feb 20.
    An arms-race against resistance: leukemic stem cells and lineage plasticity.
    Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Andreas Trumpp.
      Acute myeloid leukemia (AML) therapy is undergoing rapid development, but primary and acquired resistance to therapy complicates the prospect of a durable cure. Recent functional and single-cell multi-omics approaches have greatly expanded our knowledge of the diversity of lineage trajectories in AML settings. AML cells range from undifferentiated stem-like cells to more differentiated myeloid or megakaryocyte/erythroid cells. Current clinically relevant drugs predominantly target the myeloid progenitor lineage, while monocyte- or stem cell-like states can evade current AML treatment and may be targeted in the future with lineage-specific inhibitors. The extent of aberrant lineage plasticity upon therapeutic pressure in AML cells in conjunction with hijacking of normal differentiation pathways is still a poorly understood topic. Insights into the mechanisms of lineage plasticity of AML stem cells could identify both therapy-specific and cross-drug resistance pathways and reveal novel strategies to overcome them.
    Keywords:  AML; LSC; lineage differentiation; plasticity; resistance; venetoclax
    DOI:  https://doi.org/10.1002/1878-0261.13606
  3. Am J Hematol. 2024 Feb 21.
    Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML.
    Corentin Orvain, Naveed Ali, Megan Othus, Eduardo Rodríguez-Arbolí, Filippo Milano, Calvin M Le, Brenda M Sandmaier, Bart L Scott, Frederick R Appelbaum, Roland B Walter.
      Multiparameter flow cytometry (MFC) measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) independently predicts poor outcomes in acute myeloid leukemia (AML). Conversely, its prognostic value in the newly defined disease entity, myelodysplastic neoplasm (MDS)/AML is unknown. To assess the relationship between disease type, pre-HCT MRD, and post-HCT outcomes, we retrospectively analyzed 1265 adults with MDS/AML (n = 151) or AML (n = 1114) who received a first allograft in first or second morphologic remission at a single institution between April 2006 and March 2023. At 3 years, relapse rates (29% for MDS/AML vs. 29% for AML, p = .98), relapse-free survival (RFS; 50% vs. 55%, p = .22), overall survival (OS; 52% vs. 60%, p = .073), and non-relapse mortality (22% vs. 16%, p = .14) were not statistically significantly different. However, a significant interaction was found between pre-HCT MFC MRD and disease type (MDS/AML vs. AML) for relapse (p = .009), RFS (p = .011), and OS (p = .039). The interaction models indicated that the hazard ratios (HRs) for the association between pre-HCT MRD and post-HCT outcomes were lower in patients with MDS/AML (for relapse: HR = 1.75 [0.97-3.15] in MDS/AML vs. 4.13 [3.31-5.16] in AML; for RFS: HR = 1.58 [1.02-2.45] vs. 2.98 [2.48-3.58]; for OS: HR = 1.50 [0.96-2.35] vs. 2.52 [2.09-3.06]). On the other hand, residual cytogenetic abnormalities at the time of HCT were equally informative in MDS/AML as in AML patients. Our data indicate that MFC-based pre-HCT MRD testing, but not testing for residual cytogenetic abnormalities, is less informative for MDS/AML than AML patients when used for prognostication of post-HCT outcomes.
    DOI:  https://doi.org/10.1002/ajh.27259
  4. Blood. 2024 Feb 26. pii: blood.2023021570. [Epub ahead of print]
    CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression.
    Mariam Murtadha, Miso Park, Yinghui Zhu, Enrico Caserta, Ottavio Napolitano, Theophilus Tandoh, Milad Moloudizargari, Alex Pozhitkov, Mahmoud K Singer, Ada Alice Dona, Hawa Vahed, Asaul Gonzalez, Kevin Ly, Ching Ouyang, James Sanchez, Lokesh Nigam, Amanda Duplan, Arnab Chowdhury, Lucy Y Ghoda, Ling Li, Bin Zhang, Amrita Y Krishnan, Guido Marcucci, John C Williams, Flavia Pichiorri.
      Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that IFNγ reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFNγ-induced CD38 upregulation depends on IRF-1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T cell engager (BN-CD38) designed to promote an effective immunological synapse between both CD8 and CD4 T cells and CD38pos AML cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts leading to T cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFNγ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, while BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multi-lineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.
    DOI:  https://doi.org/10.1182/blood.2023021570
  5. Med Oncol. 2024 Feb 23. 41(3): 80
    Venetoclax with decitabine or azacitidine in relapsed or refractory acute myeloid leukemia.
    Ian M Bouligny, Graeme Murray, Michael Doyel, Tilak Patel, Josh Boron, Valerie Tran, Juhi Gor, Yiwei Hang, Yanal Alnimer, Thuy Ho, Kyle Zacholski, Chad Venn, Nolan A Wages, Steven Grant, Keri R Maher.
      Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS, KRAS, and FLT3-ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.
    Keywords:  AML; Azacitidine; Decitabine; Refractory; Relapsed; Venetoclax
    DOI:  https://doi.org/10.1007/s12032-024-02302-y
  6. Am J Hematol. 2024 Feb 23.
    Risk models in myelofibrosis-the past, present, and future.
    Ayalew Tefferi, Alessandro M Vannucchi.
      Risk models in myelofibrosis (MYSEC-PM) or primary myelofibrosis (IPSS, DIPSS, DIPSS+, MIPSS70, MIPSS70+, MIPSSv2, GIPSS).
    DOI:  https://doi.org/10.1002/ajh.27270
  7. Am J Hematol. 2024 Feb 20.
    Venetoclax in the treatment of acute myeloid leukemia: Beyond VIALE-A.
    Naseema Gangat, Ayalew Tefferi.
      Venetoclax and hypomethylating agent therapy in acute myeloid leukemia.
    DOI:  https://doi.org/10.1002/ajh.27256
  8. Leukemia. 2024 Feb 22.
    Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
    Daniel J Olivieri, Megan Othus, Corentin Orvain, Eduardo Rodríguez-Arbolí, Filippo Milano, Brenda M Sandmaier, Irum Khan, Chris Davis, Ryan S Basom, Frederick R Appelbaum, Roland B Walter.
      Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.
    DOI:  https://doi.org/10.1038/s41375-024-02172-3
  9. Am J Hematol. 2024 Feb 22.
    Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT.
    Nicola Polverelli, Edouard F Bonneville, Liesbeth C de Wreede, Linda Koster, Nicolaus Martin Kröger, Thomas Schroeder, Régis Peffault de Latour, Jakob Passweg, Katja Sockel, Annoek E C Broers, Andrew Clark, Peter Dreger, Didier Blaise, Ibrahim Yakoub-Agha, Soeren Lykke Petersen, Jürgen Finke, Patrice Chevallier, Grzegorz Helbig, Werner Rabitsch, Simona Sammassimo, Luca Arcaini, Domenico Russo, Joanna Drozd-Sokolowska, Kavita Raj, Marie Robin, Giorgia Battipaglia, Tomasz Czerw, Juan Carlos Hernández-Boluda, Donal P McLornan.
      Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.
    DOI:  https://doi.org/10.1002/ajh.27262
  10. bioRxiv. 2024 Feb 08. pii: 2024.02.04.578798. [Epub ahead of print]
    Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation.
    Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Kasiani C Myers, Matthew T Weirauch, H Leighton Grimes, Daniel T Starczynowski, Amit Verma, Nathan Salomonis.
      The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1 -mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1 -like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1 -like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1 -like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations.
    Statement of significance: Using a new in silico strategy we reveal counteracting determinants of patient survival in Acute Myeloid Leukemia that co-opt well-defined mutation-dependent splicing programs. Broad poor-prognosis splicing and leukemia stem cell survival could be rescued through pharmacological inhibition (PRMT5) or target deletion (IRAK4), opening the door for new precision therapies.
    Competing Interests: Conflict-of-interest disclosure: DTS. serves on the scientific advisory board at Kurome Therapeutics; is a consultant for and/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics; and has equity in Kurome Therapeutics. AV has received research funding from GlaxoSmithKline, BMS, Jannsen, Incyte, MedPacto, Celgene, Novartis, Curis, Prelude and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Throws Exception and Stelexis Therapeutics.
    DOI:  https://doi.org/10.1101/2024.02.04.578798
  11. Cancers (Basel). 2024 Feb 07. pii: 705. [Epub ahead of print]16(4):
    Infrequent Presentations of Chronic NPM1-Mutated Myeloid Neoplasms: Clinicopathological Features of Eight Cases from a Single Institution and Review of the Literature.
    Sandra Castaño-Díez, Francesca Guijarro, Mònica López-Guerra, Amanda Isabel Pérez-Valencia, Marta Gómez-Núñez, Dolors Colomer, Marina Díaz-Beyá, Jordi Esteve, María Rozman.
      Non-acute myeloid neoplasms (MNs) with NPM1 mutations (NPM1mut-MNs) pose a diagnostic and therapeutic dilemma, primarily manifesting as chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS). The classification and treatment approach for these conditions as acute myeloid leukemia (AML) are debated. We describe eight cases of atypical NPM1mut-MNs from our institution and review the literature. We include a rare case of concurrent prostate carcinoma and MN consistent with chronic eosinophilic leukemia, progressing to myeloid sarcoma of the skin. Of the remaining seven cases, five were CMML and two were MDS. NPM1 mutations occur in 3-5% of CMML and 1-6% of MDS, with an increased likelihood of rapid evolution to AML. Their influence on disease progression varies, and their prognostic significance in non-acute MNs is less established than in AML. Non-acute MNs with NPM1 mutations may display an aggressive clinical course, emphasizing the need for a comprehensive diagnosis integrating clinical and biological data. Tailoring patient management on an individualized basis, favoring intensive treatment aligned with AML protocols, is crucial, regardless of blast percentage. Research on the impact of NPM1 mutations in non-acute myeloid neoplasms is ongoing, requiring challenging prospective studies with substantial patient cohorts and extended follow-up periods for validation.
    Keywords:  NPM1; myeloid neoplasm (MN)atypical presentation
    DOI:  https://doi.org/10.3390/cancers16040705
  12. Bone Marrow Transplant. 2024 Feb 21.
    Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients - A clinical trial to registry data comparison.
    Dietrich Wilhelm Beelen, Simona Iacobelli, Linda Koster, Dirk-Jan Eikema, Anja van Biezen, Friedrich Stölzel, Fabio Ciceri, Wolfgang Bethge, Peter Dreger, Eva-Maria Wagner-Drouet, Péter Reményi, Matthias Stelljes, Miroslaw Markiewicz, Donal P McLornan, Ibrahim Yakoub-Agha, Mohamad Mohty.
      A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
    DOI:  https://doi.org/10.1038/s41409-024-02241-2
  13. Blood. 2024 Feb 22. 143(8): 657-658
    A new SAGA for AML: targeting SGF29 in AML.
    Jeetayu Biswas, Omar Abdel-Wahab.
      
    DOI:  https://doi.org/10.1182/blood.2023023442
  14. Clin Cancer Res. 2024 Feb 22.
    Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations.
    Malathi Kandarpa, Dan Robinson, Yi-Mi Wu, Tingting Qin, Kristen Pettit, Qing Li, Gary Luker, Maureen Sartor, Arul Chinnaiyan, Moshe Talpaz.
       PURPOSE: Myeloproliferative neoplasms (MPNs) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR and MPL are considered drivers of Bcr-Abl-ve MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF) and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear.
    EXPERIMENTAL DESIGN: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1711 genes for mutations along with whole transcriptome RNA-seq of 137 MPN patients.
    RESULTS: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N=106) and ET/PV/PrePMF (N=31), respectively. Overt MF had more mutations compared to ET/PV/prePMF (5 vs 4 per subject, P=0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1), and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2 and NF1, were exclusive to MF. Advancing age, higher DIPSS and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets, and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2 and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells.
    CONCLUSIONS: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression, and potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0372
  15. Ann Hematol. 2024 Feb 23.
    Pretransplantation predictors of survival in nonremission acute myeloid leukemia treated with haploidentical transplantation using steroid-based GVHD prophylaxis.
    Masahiro Teramoto, Hiroya Tamaki, Katsuji Kaida, Mami Samori, Saki Takahashi-Hirata, Nobuto Utsunomiya, Atsushi Katayama, Keiko Fukunaga, Takayuki Inoue, Kyoko Yoshihara, Kazuhiro Ikegame, Masaya Okada, Satoshi Yoshihara.
      Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo.
    Keywords:  Albumin; Complete-remission history; Haploidentical hematopoietic cell transplantation; Nonremission acute myeloid leukemia; Risk factors; Survival
    DOI:  https://doi.org/10.1007/s00277-024-05654-7
  16. Leukemia. 2024 Feb 20.
    Germline CHEK2 mutations in patients with myeloid neoplasms.
    Lucie Freiman, Lise Larcher, Giulia Tueur, Nadia Vasquez, Mélanie Da Costa, Matthieu Duchmann, Emmanuel Raffoux, Lionel Adès, Pierre Fenaux, Jean Soulier, Nicolas Duployez, Emmanuelle Clappier, Marie Sébert.
      
    DOI:  https://doi.org/10.1038/s41375-024-02179-w
  17. Cancer Res Commun. 2024 Feb 23.
    Single-Cell CD4 and CD8 T Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy.
    Jessica L Root, Poonam N Desai, Christopher Ly, Bofei Wang, Fatima Zahra Jelloul, Jing Zhou, Sean Mackay, Mansour Alfayez, Jairo Matthews, Sherry Pierce, Patrick K Reville, Naval Daver, Hussein A Abbas.
      Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T cell anti-leukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of relapsed/refractory (RelRef) AML patients treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy using azacitidine and nivolumab (Aza/Nivo). We utilized the single cell polyfunctional multiplexed immune assay IsoPlexis to evaluate the CD4 and CD8 T cells in peripheral blood and bone marrow samples collected before and after immunotherapy. This revealed at a pseudobulk level that the CD4 T cells exhibited higher functional activity post-immunotherapy (post-IO), suggesting that CD4-directed therapies may play a role in RelRef AML. Additional single-cell analysis revealed significant differences in baseline polyfunctionality in bone marrows of responders as compared to non-responders for both CD4 and CD8 T cells. Overall, this study highlights the impact of polyfunctional assessment in understanding CD4 and CD8 dynamics in contexts of therapy in AML.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0402
  18. Blood Cancer J. 2024 Feb 20. 14(1): 32
    Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).
    Talha Badar, Ahmad Nanaa, Ehab Atallah, Rory M Shallis, Sacchi de Camargo Correia Guilherme, Aaron D Goldberg, Antoine N Saliba, Anand Patel, Jan P Bewersdorf, Adam S DuVall, Danielle Bradshaw, Yasmin Abaza, Guru Subramanian Guru Murthy, Neil Palmisiano, Amer M Zeidan, Vamsi Kota, Mark R Litzow.
      
    DOI:  https://doi.org/10.1038/s41408-024-01000-2
  19. Leukemia. 2024 Feb 17.
    Clinical impact of genetic alterations including germline DDX41 mutations in MDS/low-blast count AML patients treated with azacitidine-based regimens.
    Marie Sébert, Lucie Freiman, Cendrine Chaffaut, Agnès Guerci, Pierre Peterlin, Sylvain Thépot, Odile Beyne-Rauzy, Sophie Park, Thomas Cluzeau, Fatiha Chermat, Pierre Fenaux, Claude Preudhomme, Emmanuelle Clappier, Sylvie Chevret, Lionel Adès, Nicolas Duployez, Matthieu Duchmann.
      
    DOI:  https://doi.org/10.1038/s41375-024-02180-3
  20. Leukemia. 2024 Feb 20.
    Deregulation of the p19/CDK4/CDK6 axis in Jak2V617F megakaryocytes accelerates the development of myelofibrosis.
    Hélène Duparc, Delphine Muller, Laure Gilles, Agathe L Chédeville, Mira El Khoury, Rose Guignard, Najet Debili, Monika Wittner, Alexandre Kauskot, Florence Pasquier, Iléana Antony-Debré, Caroline Marty, William Vainchenker, Isabelle Plo, Hana Raslova.
      
    DOI:  https://doi.org/10.1038/s41375-024-02170-5
  21. Leukemia. 2024 Feb 23.
    The evolution of preclinical models for myelodysplastic neoplasms.
    Alain Mina, Steven Pavletic, Peter D Aplan.
      Myelodysplastic Neoplasms (MDS) are a group of clonal disorders characterized by ineffective hematopoiesis and morphologic dysplasia. Clinical manifestations of MDS vary widely and are dictated in large part by a range of genetic aberrations. The lack of robust in vitro models for MDS has limited the ability to conduct high throughput drug screens, which in turn has hampered the development of novel therapies for MDS. There are very few well-characterized MDS cell lines, and the available cell lines expand poorly in vitro. Conventional xenograft mouse models can provide an in vivo vessel to provide growth of cancer cells, but human MDS cells engraft poorly. Three-dimensional (3D) scaffold models that form human "ossicles" represent a promising new approach and can reproduce the intricate communication between hematopoietic stem and progenitor cells and their environment. Genetically engineered mice utilize specific mutations and may not represent the entire array of human MDS; however, genetically engineered mice provided in vivo proof of principle for novel agents such as luspatercept, demonstrating the clinical utility of this approach. This review offers an overview of available preclinical MDS models and potential approaches to accelerate accurate clinical translation.
    DOI:  https://doi.org/10.1038/s41375-024-02181-2
  22. Nature. 2024 Feb 21.
    Mechanisms of action and resistance in histone methylation-targeted therapy.
    Makoto Yamagishi, Yuta Kuze, Seiichiro Kobayashi, Makoto Nakashima, Satoko Morishima, Toyotaka Kawamata, Junya Makiyama, Kako Suzuki, Masahide Seki, Kazumi Abe, Kiyomi Imamura, Eri Watanabe, Kazumi Tsuchiya, Isao Yasumatsu, Gensuke Takayama, Yoshiyuki Hizukuri, Kazumi Ito, Yukihiro Taira, Yasuhito Nannya, Arinobu Tojo, Toshiki Watanabe, Shinji Tsutsumi, Yutaka Suzuki, Kaoru Uchimaru.
      Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.
    DOI:  https://doi.org/10.1038/s41586-024-07103-x
  23. Blood Cancer J. 2024 Feb 19. 14(1): 31
    Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial.
    Eolia Brissot, Myriam Labopin, Helene Labussière, Gaelle Fossard, Patrice Chevallier, Thierry Guillaume, Ibrahim Yakoub-Agha, Micha Srour, Claude-Eric Bulabois, Anne Huynh, Sylvain Chantepie, Anne-Lise Menard, Marie-Therese Rubio, Patrice Ceballos, Rémy Dulery, Sabine Furst, Florent Malard, Didier Blaise, Mohamad Mohty.
      The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.
    DOI:  https://doi.org/10.1038/s41408-024-00990-3
  24. Leukemia. 2024 Feb 23.
    Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.
    Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A Yassin, Delphine Rea, Franck E Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese.
      The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001-2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd-3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.
    DOI:  https://doi.org/10.1038/s41375-024-02183-0
  25. Science. 2024 Feb 23. 383(6685): eadi3808
    An immunogenetic basis for lung cancer risk.
    FinnGen§
      Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.
    DOI:  https://doi.org/10.1126/science.adi3808
  26. Sci Transl Med. 2024 Feb 21. 16(735): eadi1501
    Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease.
    Marie Czech, Sophia Schneider, Nina Peltokangas, Nadia El Khawanky, Sakhila Ghimire, Geoffroy Andrieux, Jan Hülsdünker, Máté Krausz, Michele Proietti, Lukas M Braun, Tamina Rückert, Marlene Langenbach, Dominik Schmidt, Ina Martin, Valentin Wenger, Enrique de Vega, Eileen Haring, Mohsen Pourjam, Dietmar Pfeifer, Annette Schmitt-Graeff, Bodo Grimbacher, Konrad Aumann, Brigitte Kircher, Herbert Tilg, Manuela Raffatellu, Erik Thiele Orberg, Georg Häcker, Justus Duyster, Natalie Köhler, Ernst Holler, David Nachbaur, Melanie Boerries, Romana R Gerner, Dominic Grün, Robert Zeiser.
      Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.
    DOI:  https://doi.org/10.1126/scitranslmed.adi1501
  27. Nat Methods. 2024 Feb 19.
    Generation of complex bone marrow organoids from human induced pluripotent stem cells.
    Stephanie Frenz-Wiessner, Savannah D Fairley, Maximilian Buser, Isabel Goek, Kirill Salewskij, Gustav Jonsson, David Illig, Benedicta Zu Putlitz, Daniel Petersheim, Yue Li, Pin-Hsuan Chen, Martina Kalauz, Raffaele Conca, Michael Sterr, Johanna Geuder, Yoko Mizoguchi, Remco T A Megens, Monika I Linder, Daniel Kotlarz, Martina Rudelius, Josef M Penninger, Carsten Marr, Christoph Klein.
      The human bone marrow (BM) niche sustains hematopoiesis throughout life. We present a method for generating complex BM-like organoids (BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist of key cell types that self-organize into spatially defined three-dimensional structures mimicking cellular, structural and molecular characteristics of the hematopoietic microenvironment. Functional properties of BMOs include the presence of an in vivo-like vascular network, the presence of multipotent mesenchymal stem/progenitor cells, the support of neutrophil differentiation and responsiveness to inflammatory stimuli. Single-cell RNA sequencing revealed a heterocellular composition including the presence of a hematopoietic stem/progenitor (HSPC) cluster expressing genes of fetal HSCs. BMO-derived HSPCs also exhibited lymphoid potential and a subset demonstrated transient engraftment potential upon xenotransplantation in mice. We show that the BMOs could enable the modeling of hematopoietic developmental aspects and inborn errors of hematopoiesis, as shown for human VPS45 deficiency. Thus, iPSC-derived BMOs serve as a physiologically relevant in vitro model of the human BM microenvironment to study hematopoietic development and BM diseases.
    DOI:  https://doi.org/10.1038/s41592-024-02172-2
  28. Nat Protoc. 2024 Feb 23.
    Reconstructing phylogenetic trees from genome-wide somatic mutations in clonal samples.
    Tim H H Coorens, Michael Spencer Chapman, Nicholas Williams, Inigo Martincorena, Michael R Stratton, Jyoti Nangalia, Peter J Campbell.
      Phylogenetic trees are a powerful means to display the evolutionary history of species, pathogens and, more recently, individual cells of the human body. Whole-genome sequencing of laser capture microdissections or expanded stem cells has allowed the discovery of somatic mutations in clones, which can be used as natural barcodes to reconstruct the developmental history of individual cells. Here we describe Sequoia, our pipeline to reconstruct lineage trees from clones of normal cells. Candidate somatic mutations are called against the human reference genome and filtered to exclude germline mutations and artifactual variants. These filtered somatic mutations form the basis for phylogeny reconstruction using a maximum parsimony framework. Lastly, we use a maximum likelihood framework to explicitly map mutations to branches in the phylogenetic tree. The resulting phylogenies can then serve as a basis for many subsequent analyses, including investigating embryonic development, tissue dynamics in health and disease, and mutational signatures. Sequoia can be readily applied to any clonal somatic mutation dataset, including single-cell DNA sequencing datasets, using the commands and scripts provided. Moreover, Sequoia is highly flexible and can be easily customized. Typically, the runtime of the core script ranges from minutes to an hour for datasets with a moderate number (50,000-150,000) of variants. Competent bioinformatic skills, including in-depth knowledge of the R programming language, are required. A high-performance computing cluster (one that is capable of running mutation-calling algorithms and other aspects of the analysis at scale) is also required, especially if handling large datasets.
    DOI:  https://doi.org/10.1038/s41596-024-00962-8
  29. Curr Hematol Malig Rep. 2024 Feb 23.
    Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Strategies to Optimize Success and New Directions.
    Delphine Rea, Sofiane Fodil, Etienne Lengline, Emmanuel Raffoux, Jean-Michel Cayuela.
       PURPOSE OF REVIEW: The discovery that patients suffering from chronic myeloid leukemia who obtain deep and long-lasting molecular responses upon treatment with tyrosine kinase inhibitors may maintain their disease silent for many years after therapy discontinuation launched the era of treatment-free remission as a key management goal in clinical practice. The purpose of this review on treatment-free remission is to discuss clinical advances, highlight knowledge gaps, and describe areas of research.
    RECENT FINDINGS: Patients in treatment-free remission are a minority, and it is believed that some may still retain a reservoir of leukemic stem cells; thus, whether they can be considered as truly cured is uncertain. Strengthening BCR::ABL1 inhibition increases deep molecular responses but is not sufficient to improve treatment-free remission, and we lack biomarkers to identify and specifically target residual cells with aggressive potential. Another level of complexity resides in the intra- and inter-patient clonal heterogeneity of minimal residual disease and characteristics of the bone marrow environment. Finding determinants of deep molecular responses achievement and elucidating varying biological mechanisms enabling either post-tyrosine kinase inhibitor chronic myeloid leukemia control or relapse may help develop innovative and safe therapies. In the light of the increasing prevalence of CML, targeting the residual leukemic stem cell pool is thought to be the key.
    Keywords:  Chronic myeloid leukemia; Cure; Leukemic stem cells; Treatment-free remission; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1007/s11899-024-00728-9
  30. J Clin Invest. 2024 Feb 22. pii: e172468. [Epub ahead of print]
    Ectopic expression of transcription factor ONECUT3 drives complex karyotype in Myelodysplastic Syndromes.
    Yingwan Luo, Xiaomin Feng, Wei Lang, Weihong Xu, Wei Wang, Chen Mei, Li Ye, Shuanghong Zhu, Lu Wang, Xinping Zhou, Huimin Zeng, Liya Ma, Yanling Ren, Jie Jin, Rongzhen Xu, Gang Huang, Hongyan Tong.
      Chromosomal instability is a prominent biological feature of Myelodysplastic Syndromes (MDS), with over 50% of MDS patients harboring chromosomal abnormalities or a complex karyotype. Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified a ectopic expression of transcription factor ONECUT3, associated with complex karyotypes and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of Chromosome Passenger Complex (CPC) accumulation besides the cell equator and midbody during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the Homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8, and transcriptionally activated these two genes. A novel lead compound C5484617, was identified that functionally targeted the HOX domain of ONECUT3 inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognosis and therapeutic roles for targeting high-risk MDS patients with complex karyotype.
    Keywords:  Bone marrow; Genetic instability; Hematology
    DOI:  https://doi.org/10.1172/JCI172468
  31. Cancer. 2024 Feb 19.
    Myelofibrosis: Current unmet needs, emerging treatments, and future perspectives.
    Claire N Harrison, Jean-Jacques Kiladjian, Steffen Koschmieder, Francesco Passamonti.
      The current standard-of-care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic-hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high-risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first-line therapies (likely highly novel or combination strategies) for intermediate-risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF.
    Keywords:  clinical end points; combination therapy; disease modification; essential thrombocythemia; myelofibrosis; polycythemia vera; unmet need
    DOI:  https://doi.org/10.1002/cncr.35244
  32. Haematologica. 2024 Feb 22.
    Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive post-remission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia.
    Sonia Jaramillo, Johannes Krisam, Lucian Le Cornet, Markus Kratzmann, Lukas Baumann, Olga Eissymont, Martina Crysandt, Martin Görner, Sabine Kayser, Stefan Krause, Christoph Schliemann, Tobias Gaska, Martin Kaufmann, Jens Chemnitz, Markus Schaich, Alexander Hoellein, Uwe Platzbecker, Meinhard Kieser, Carsten Müller-Tidow, Richard F Schlenk.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284346
  33. Nat Cell Biol. 2024 Feb 23.
    Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
      
    DOI:  https://doi.org/10.1038/s41556-024-01350-w
  34. Nat Metab. 2024 Feb 20.
    Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
    Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski, Jeffrey D Rothstein, Evanna L Mills, Edward T Chouchani.
      Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-024-00981-5
  35. Am J Hematol. 2024 Feb 23.
    NPM1-mutated myeloid neoplasm with low percentage of blasts.
    Brunangelo Falini, Patrizia Chiusolo, Luana Fianchi, Livio Pagano.
      
    DOI:  https://doi.org/10.1002/ajh.27260
  36. Sci Adv. 2024 Feb 23. 10(8): eadk3127
    Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery.
    Anthony K N Chan, Li Han, Christopher D Delaney, Xueer Wang, Elizaveta Mukhaleva, Mingli Li, Lu Yang, Sheela Pangeni Pokharel, Nicole Mattson, Michelle Garcia, Bintao Wang, Xiaobao Xu, Leisi Zhang, Priyanka Singh, Zeinab Elsayed, Renee Chen, Benjamin Kuang, Jinhui Wang, Yate-Ching Yuan, Bryan Chen, Lai N Chan, Steven T Rosen, David Horne, Markus Müschen, Jianjun Chen, Nagarajan Vaidehi, Scott A Armstrong, Rui Su, Chun-Wei Chen.
      Epigenetic dysregulation has been reported in multiple cancers including leukemias. Nonetheless, the roles of the epigenetic reader Tudor domains in leukemia progression and therapy remain unexplored. Here, we conducted a Tudor domain-focused CRISPR screen and identified SGF29, a component of SAGA/ATAC acetyltransferase complexes, as a crucial factor for H3K9 acetylation, ribosomal gene expression, and leukemogenesis. To facilitate drug development, we integrated the CRISPR tiling scan with compound docking and molecular dynamics simulation, presenting a generally applicable strategy called CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD). Using this approach, we identified a lead inhibitor that selectively targets SGF29's Tudor domain and demonstrates efficacy against leukemia. Furthermore, we propose that the structural genetics approach used in our study can be widely applied to diverse fields for de novo drug discovery.
    DOI:  https://doi.org/10.1126/sciadv.adk3127
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