bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒07‒23
forty papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
  2. Role of IL8 in myeloid malignancies.
  3. AML Samples Show High Concordance in Detection of Mutations by NGS at Local Institutions versus Central Laboratories.
  4. Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
  5. Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy.
  6. SETBP1 is dispensable for normal and malignant hematopoiesis.
  7. Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.
  8. Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.
  9. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort.
  10. A SINGLE-CELL TAXONOMY PREDICTS INFLAMMATORY NICHE REMODELING TO DRIVE TISSUE FAILURE AND OUTCOME IN HUMAN AML.
  11. Morphologic, immunophenotypic, molecular genetic, and clinical characterization in patients with SRSF2-mutated acute myeloid leukemia.
  12. Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival.
  13. Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance.
  14. How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?
  15. Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages.
  16. IDH2 mutations in acute myeloid leukemia.
  17. Influence of conditioning regimen intensity on outcomes post-allogeneic hematopoietic cell transplantation for acute myeloid leukemia in complete morphological remission.
  18. miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.
  19. Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo.
  20. FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.
  21. XPO1 is a new target of homoharringtonine (HHT): Making NPMc+ AML cells much more sensitive to HHT treatment.
  22. The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study.
  23. The role of the MDM2/p53 axis in anti-tumor immune responses.
  24. Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia.
  25. Expression of long non-coding RNA UCA1 and its clinical relevance in paediatric acute myeloid leukemia.
  26. Escape from T-cell targeting immunotherapies in acute myeloid leukemia.
  27. DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias.
  28. Chimeric antigen receptor T cells for acute myeloid leukemia.
  29. BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice.
  30. Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.
  31. Clonal hematopoiesis in VEXAS syndrome.
  32. SF3B1 mutation and ATM deletion co-drive leukemogenesis via centromeric R-loop dysregulation.
  33. UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
  34. Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.
  35. An in vitro model of human hematopoiesis identifies a regulatory role for the aryl hydrocarbon receptor.
  36. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
  37. FLAG based v/s Standard 3 + 7 induction therapy in treatment naïve Acute Myeloid Leukemia: Time to think "beyond anthracyclines".
  38. Early cessation of calcineurin inhibitors is feasible post haploidentical blood stem cell transplant-the ANZHIT-1 study.
  39. Histone demethylase PHF8 facilitates the development of chronic myeloid leukaemia by directly targeting BCR::ABL1.
  40. Computational analysis of peripheral blood smears detects disease-associated cytomorphologies.
  1. Br J Haematol. 2023 Jul 16.
    Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    Friederike Pastore, Hanna Gittinger, Susanne Raab, Sebastian Tschuri, Bianka Ksienzyk, Nikola P Konstandin, Stephanie Schneider, Maja Rothenberg-Thurley, Hans-Peter Horny, Martin Werner, Maria C Sauerland, Susanne Amler, Dennis Görlich, Wolfgang E Berdel, Bernhard Wörmann, Jan Braess, Wolfgang Hiddemann, Johanna Tischer, Tobias Herold, Klaus H Metzeler, Karsten Spiekermann.
      Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup.
    Keywords:  AMKL; AML; AML M7; allo-HSCT; cytogenetic and molecular landscape; prognosis
    DOI:  https://doi.org/10.1111/bjh.18982
  2. Leuk Lymphoma. 2023 Jul 19. 1-10
    Role of IL8 in myeloid malignancies.
    Nandini Ramachandra, Malini Gupta, Leya Schwartz, Tihomira Todorova, Aditi Shastri, Britta Will, Ulrich Steidl, Amit Verma.
      Aberrant overexpression of Interleukin-8 (IL8) has been reported in Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPNs) and other myeloid malignancies. IL8 (CXCL8) is a CXC chemokine that is secreted by aberrant hematopoietic stem and progenitors as well as other cells in the tumor microenvironment. IL8 can bind to CXCR1/CXCR2 receptors and activate oncogenic signaling pathways, and also increase the recruitment of myeloid derived suppressor cells to the tumor microenvironment. IL8/CXCR1/2 overexpression has been associated with poorer prognosis in MDS and AML and increased bone marrow fibrosis in Myelofibrosis. Preclinical studies have demonstrated benefit of inhibiting the IL8/CXCR1/2 pathways via restricting the growth of leukemic stem cells as well as normalizing the immunosuppressive microenvironment in tumors. Targeting the IL8-CXCR1/2 pathway is a potential therapeutic strategy in myeloid neoplasms and is being evaluated with small molecule inhibitors as well as monoclonal antibodies in ongoing clinical trials. We review the role of IL8 signaling pathway in myeloid cancers and discuss future directions on therapeutic targeting of IL8 in these diseases.
    Keywords:  AML; IL8 inhibition; Leukemic stem cells; MDS; MPN
    DOI:  https://doi.org/10.1080/10428194.2023.2232492
  3. Blood Adv. 2023 Jul 17. pii: bloodadvances.2022009008. [Epub ahead of print]
    AML Samples Show High Concordance in Detection of Mutations by NGS at Local Institutions versus Central Laboratories.
    Uma Borate, Fei Yang, Richard D Press, Amy S Ruppert, Daniel Jones, Sean Caruthers, Weiqiang Zhao, Jo-Anne Vergilio, Dean Pavlick, Luke Juckett, Brianna A Norris, Taylor Bucy, Amy Burd, Eytan M Stein, Prapti Arvind Patel, Maria R Baer, Wendy Stock, Gary J Schiller, William Blum, Tibor J Kovacsovics, Mark R Litzow, James M Foran, Nyla A Heerema, Leonard Rosenberg, Sonja Marcus, Ashley O Yocum, Mona Stefanos, Brian J Druker, Alice S Mims.
      Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations between different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this inter-laboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed AML patients enrolled in the Beat AML® Master Trial (BAMT) at two academic institutions. We analyzed the diagnostic AML samples for the detection of pathogenic myeloid mutations in eight genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (Site 1) or the GeneTrails® Comprehensive Heme Panel (Site 2) at the two institutions and compared them to the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. (FMI). The overall percent agreement was over 95% each in all eight genes, with almost perfect agreement (kappa>0.906) in all but WT1, which had substantial agreement (kappa=0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze AML patient samples enrolled in the BAMT show high concordance, a reassuring finding given the wide utilization of NGS for therapeutic decision-making in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009008
  4. Nat Cancer. 2023 Jul 20.
    Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
    Tim H H Coorens, Grace Collord, Taryn D Treger, Stuart Adams, Emily Mitchell, Barbara Newman, Gad Getz, Anna L Godfrey, Jack Bartram, Sam Behjati.
      Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1-4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.
    DOI:  https://doi.org/10.1038/s43018-023-00604-0
  5. Onco Targets Ther. 2023 ;16 571-576
    Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy.
    Seiichiro Katagiri, Nahoko Furuya, Daigo Akahane, SungGi Chi, Yosuke Minami, Yuka Harada, Hironori Harada, Akihiko Gotoh.
      We performed sequential molecular analyses of a 75-year-old woman with de novo FLT3-ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, FLT3-ITD, NPM1, DNMT3A, and IDH2 mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. FLT3-ITD and NPM1 mutations were persistently positive, and the patient received gilteritinib therapy. Although the FLT3-ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and CBL mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the FLT3-ITD clone was detected again. Gilteritinib treatment was restarted, and FLT3-ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) FLT3-ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.
    Keywords:  CBL; FLT3-ITD; clonal hematopoiesis; gilteritinib; monosomy 7
    DOI:  https://doi.org/10.2147/OTT.S417137
  6. Leukemia. 2023 Jul 18.
    SETBP1 is dispensable for normal and malignant hematopoiesis.
    Atsushi Tanaka, Koutarou Nishimura, Wataru Saika, Ayana Kon, Yui Koike, Hiromi Tatsumi, June Takeda, Masaki Nomura, Weijia Zang, Manabu Nakayama, Masashi Matsuda, Hiromi Yamazaki, Miki Fukumoto, Hiromi Ito, Yasutaka Hayashi, Toshio Kitamura, Hiroshi Kawamoto, Akifumi Takaori-Kondo, Haruhiko Koseki, Seishi Ogawa, Daichi Inoue.
      SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.
    DOI:  https://doi.org/10.1038/s41375-023-01970-5
  7. Cell Rep. 2023 Jul 16. pii: S2211-1247(23)00805-7. [Epub ahead of print]42(7): 112794
    Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.
    Fenghua Qian, Shaneice K Nettleford, Jiayan Zhou, Brooke E Arner, Molly A Hall, Arati Sharma, Charyguly Annageldiyev, Randy M Rossi, Diwakar B Tukaramrao, Deborpita Sarkar, Shailaja Hegde, Ujjawal H Gandhi, Emily R Finch, Laura Goodfield, Michael D Quickel, David F Claxton, Robert F Paulson, K Sandeep Prabhu.
      Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44-/- LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.
    Keywords:  CP: Cancer; CRTH2; KRAS; MAP kinase; PPAR; RTK; leukemia; p53; prostaglandins; selenium
    DOI:  https://doi.org/10.1016/j.celrep.2023.112794
  8. Pediatr Blood Cancer. 2023 Jul 21. e30584
    Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.
    Todd M Cooper, Todd A Alonzo, Sarah K Tasian, Matthew A Kutny, Johann Hitzler, Jessica A Pollard, Richard Aplenc, Soheil Meshinchi, E Anders Kolb.
      During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.
    Keywords:  AML; chemotherapy; clinical trials; molecular diagnosis and therapy; sub-specialty classification
    DOI:  https://doi.org/10.1002/pbc.30584
  9. Leukemia. 2023 Jul 15.
    Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort.
    Georgia Metzgeroth, Laurenz Steiner, Nicole Naumann, Johannes Lübke, Sebastian Kreil, Alice Fabarius, Claudia Haferlach, Torsten Haferlach, Wolf-Karsten Hofmann, Nicholas C P Cross, Juliana Schwaab, Andreas Reiter.
      In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 109/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 109/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
    DOI:  https://doi.org/10.1038/s41375-023-01958-1
  10. Blood Cancer Discov. 2023 Jul 20. pii: BCD-23-0043. [Epub ahead of print]
    A SINGLE-CELL TAXONOMY PREDICTS INFLAMMATORY NICHE REMODELING TO DRIVE TISSUE FAILURE AND OUTCOME IN HUMAN AML.
    Lanpeng Chen, Eline Pronk, Claire van Dijk, Yujie Bian, Jacqueline Feyen, Tim van Tienhoven, Meltem Yildirim, Paola Pisterzi, Madelon M E De Jong, Alejandro Bastidas, Remco M Hoogenboezem, Chiel Wevers, Eric M Bindels, Bob Löwenberg, Tom Cupedo, Mathijs A Sanders, Marc Hgp Raaijmakers.
      Cancer initiation is orchestrated by interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPCs) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors is predicted to repress high-output HSC subsets in NPM1-mutated AML, with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcome after chemotherapy across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection, but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0043
  11. Am J Clin Pathol. 2023 Jul 17. pii: aqad077. [Epub ahead of print]
    Morphologic, immunophenotypic, molecular genetic, and clinical characterization in patients with SRSF2-mutated acute myeloid leukemia.
    Joshua Tatarian, Natalie Tupper Bs, Peng Li, Julie Feusier, Maryam Abdo, Stephen Hyter, Patrick R Gonzales, Da Zhang, Janet Woodroof, Sarah Kelting, Andrew K Godwin, Wei Cui.
      OBJECTIVES: SRSF2 mutations are known to be associated with poor outcomes in myelodysplastic neoplasm, but studies on their prognostic impact on acute myeloid leukemia (AML) remain limited. In this retrospective study, we analyzed clinical and pathologic characteristics of patients with AML and correlated the outcomes with SRSF2 mutations.METHODS: We characterized the morphologic, immunophenotypic, molecular, and clinical findings in AML with mutated SRSF2 and compared them with SRSF2 wild-type (WT) myeloid neoplasms (MNs).
    RESULTS: Using next-generation sequencing, we identified 134 patients with MNs and SRSF2 mutations (85 with AML and 49 with MNs) in addition to 342 SRSF2-WT AMLs. Fifty-two (62%) patients with altered SRSF2 demonstrated a variable degree of morphologic dysplasia. The most frequent immunophenotypic aberrancies in SFSF2-mutant AML included diminished CD33 expression and overexpression of CD7, CD56, or CD123, similar to WT AML. More IDH1/2 (P = .015) and NPM1 (P = .002) mutations were seen in SRSF2-mutant AML than in SRSF2-mutant non-AML. Further, more IDH1/2, ASXL1, RUNX1, and STAG2 mutations were observed in SRSF2-mutant AML than in SRSF2-WT AML (P < .0001 to P = .001). Finally, patients with SRSF2-mutant AML showed a significantly worse overall survival (OS) than patients with SRSF2-WT AML (P < .0001), but this worse OS appeared to be rescued by allogeneic stem cell transplant (allo-SCT).
    CONCLUSIONS: Acute myeloid leukemia with altered SRSF2 shows a variable degree of morphologic dysplasia without uniform immunophenotypic aberrancies. SRSF2 mutations appear to be independent poor prognostic factors, but allo-SCT has improved the clinical outcomes in patients with SRSF2-mutant AML.
    Keywords:   SRSF2 ; AML; NGS; flow cytometry; somatic mutation
    DOI:  https://doi.org/10.1093/ajcp/aqad077
  12. J Biol Chem. 2023 Jul 14. pii: S0021-9258(23)02083-5. [Epub ahead of print] 105055
    Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival.
    Peipei Wang, Jing Wang, Shuxin Yao, Manman Cui, Ying Cheng, Weidong Liu, Zhuying Gao, Jin Hu, Jinfang Zhang, Haojian Zhang.
      Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA m6A is the most abundant post-transcriptional modification on mammalian mRNAs, and plays important roles in various physiological and pathological conditions including hematologic malignancies. We previously determined that the RNA m6A eraser ALKBH5 is necessary for the maintenance of acute myeloid leukemia (AML) stem cell function, but the post-translational modifications involved in ALKBH5 regulation remain elusive. Here, we show that deubiquitinase USP9X stabilizes ALKBH5 and promotes AML cell survival. Through the use of mass spectrometry as an unbiased approach, we identify USP9X and confirm that it directly binds to ALKBH5. USP9X stabilizes ALKBH5 by removing the K48-linked polyubiquitin chain at K57. Using human myeloid leukemia cells and a murine AML model, we find that genetic knockdown or pharmaceutical inhibition of USP9X inhibits leukemia cell proliferation, induces apoptosis, and delays AML development. Ectopic expression of ALKBH5 partially mediates the function of USP9X in AML. Overall, this study uncovers deubiquitinase USP9X as a key for stabilizing ALKBH5 expression, and reveals the important role of USP9X in AML, which provides a promising therapeutic strategy for AML treatment in the clinic.
    Keywords:  ALKBH5; Acute myeloid leukemia; Deubiquitination; RNA m(6)A; USP9X
    DOI:  https://doi.org/10.1016/j.jbc.2023.105055
  13. Commun Biol. 2023 Jul 21. 6(1): 765
    Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance.
    Huihui Fan, Feng Wang, Andy Zeng, Alex Murison, Katarzyna Tomczak, Dapeng Hao, Fatima Zahra Jelloul, Bofei Wang, Praveen Barrodia, Shaoheng Liang, Ken Chen, Linghua Wang, Zhongming Zhao, Kunal Rai, Abhinav K Jain, John Dick, Naval Daver, Andy Futreal, Hussein A Abbas.
      Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.
    DOI:  https://doi.org/10.1038/s42003-023-05120-6
  14. Cancer Drug Resist. 2023 ;6(2): 223-238
    How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?
    Salvatore Perrone, Tiziana Ottone, Nadezda Zhdanovskaya, Matteo Molica.
      FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
    Keywords:   Acute myeloid Leukemia; FLT3; TKI-inhibitor resistance; crenolanib; gilteritinib; midostaurin; quizartinib; sorafenib
    DOI:  https://doi.org/10.20517/cdr.2022.130
  15. Leukemia. 2023 Jul 19.
    Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages.
    Katherine Sturgess, Eliza Yankova, M S Vijayabaskar, Tomoya Isobe, Justyna Rak, Iwo Kucinski, Melania Barile, Natalie A Webster, Maria Eleftheriou, Rebecca Hannah, Malgorzata Gozdecka, George Vassiliou, Oliver Rausch, Nicola K Wilson, Berthold Göttgens, Konstantinos Tzelepis.
      
    DOI:  https://doi.org/10.1038/s41375-023-01965-2
  16. Leuk Lymphoma. 2023 Jul 18. 1-9
    IDH2 mutations in acute myeloid leukemia.
    Rodrick Babakhanlou, Courtney DiNardo, Gautam Borthakur.
      Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the disease, the advent of new treatment options has enriched the armamentarium of the physician to combat the disease. Mutations of the isocitrate dehydrogenase (IDHs) genes are common in AML and occur in 20-30% of cases. These mutations lead to DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation. Targeting mutant IDH, either as monotherapy or in combination with hypomethylating agents (HMAs) or BCL-2 inhibitors, has opened new avenues of therapy for these patients.This review will outline the function of IDHs and focus on the biological effects of IDH2 mutations in AML, their prognosis and treatment options.
    Keywords:  AML; Acute myeloid leukemia; IDH2 inhibitors; IDH2 mutations; enasidenib
    DOI:  https://doi.org/10.1080/10428194.2023.2237153
  17. Eur J Haematol. 2023 Jul 18.
    Influence of conditioning regimen intensity on outcomes post-allogeneic hematopoietic cell transplantation for acute myeloid leukemia in complete morphological remission.
    Tommy Alfaro Moya, Jonas Mattsson, Mats Remberger, Jeffrey H Lipton, Dennis D Kim, Auro Viswabandya, Rajat Kumar, Wilson Lam, Arjun D Law, Armin Gerbitz, Ivan Pasic, Igor Novitzky-Basso, Fotios V Michelis.
      INTRODUCTION: The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting.METHODS: We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T-cell depletion as graft-versus-host disease (GVHD) prophylaxis.
    RESULTS: Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p = .44). Two-year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p = .15). Two-year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p = .02). Two-year graft-versus-host disease relapse-free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p = .30). A propensity score-matched analysis was done matching patients for age, HLA match, in vivo T-cell depletion, and Disease Risk Index (DRI). Two-year OS was 67% for MAC, 66% for RIC (p = .95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p = .006).
    CONCLUSIONS: In the matched-related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T-cell depleted patients the outcomes of MAC and RIC were similar.
    Keywords:  MAC; RIC; acute myeloid leukemia; allogeneic stem cell transplantation; conditioning regimen intensity; outcomes; propensity-matched analysis
    DOI:  https://doi.org/10.1111/ejh.14041
  18. Cell Death Discov. 2023 Jul 15. 9(1): 249
    miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.
    Han Zhong Pei, Zhiyong Peng, Xiaomei Zhuang, Xiaobo Wang, Bo Lu, Yao Guo, Yuming Zhao, Dengyang Zhang, Yunjun Xiao, Tianshun Gao, Liuting Yu, Chunxiao He, Shunjie Wu, Suk-Hwan Baek, Zhizhuang Joe Zhao, Xiaojun Xu, Yun Chen.
      Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.
    DOI:  https://doi.org/10.1038/s41420-023-01537-4
  19. Leukemia. 2023 Jul 18.
    Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo.
    Signe Neldeborg, Johannes Frasez Soerensen, Charlotte Thornild Møller, Marie Bill, Zongliang Gao, Rasmus O Bak, Kasper Holm, Boe Sorensen, Mette Nyegaard, Yonglun Luo, Peter Hokland, Magnus Stougaard, Maja Ludvigsen, Christian Kanstrup Holm.
      Oncogenic fusion drivers are common in hematological cancers and are thus relevant targets of future CRISPR-Cas9-based treatment strategies. However, breakpoint-location variation in patients pose a challenge to traditional breakpoint-targeting CRISPR-Cas9-mediated disruption strategies. Here we present a new dual intron-targeting CRISPR-Cas9 treatment strategy, for targeting t(8;21) found in 5-10% of de novo acute myeloid leukemia (AML), which efficiently disrupts fusion genes without prior identification of breakpoint location. We show in vitro growth rate and proliferation reduction by 69 and 94% in AML t(8;21) Kasumi-1 cells, following dual intron-targeted disruption of RUNX1-RUNX1T1 compared to a non t(8;21) AML control. Furthermore, mice injected with RUNX1-RUNX1T1-disrupted Kasumi-1 cells had in vivo tumor growth reduction by 69 and 91% compared to controls. Demonstrating the feasibility of RUNX1-RUNX1T1 disruption, these findings were substantiated in isolated primary cells from a patient diagnosed with AML t(8;21). In conclusion, we demonstrate proof-of-principle of a dual intron-targeting CRISPR-Cas9 treatment strategy in AML t(8;21) without need for precise knowledge of the breakpoint location.
    DOI:  https://doi.org/10.1038/s41375-023-01950-9
  20. Br J Haematol. 2023 Jul 17.
    FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.
    J C Peschke, R Bergmann, M Mehnert, K E Gonzalez Soto, L R Loureiro, N Mitwasi, A Kegler, H Altmann, M Wobus, D Máthé, K Szigeti, A Feldmann, M Bornhäuser, M Bachmann, F Fasslrinner, C Arndt.
      Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.
    Keywords:  CAR T cells; CD135; FLT3; UniCAR; acute myeloid leukaemia
    DOI:  https://doi.org/10.1111/bjh.18971
  21. Biochem Biophys Res Commun. 2023 Jul 16. pii: S0006-291X(23)00884-7. [Epub ahead of print]675 155-161
    XPO1 is a new target of homoharringtonine (HHT): Making NPMc+ AML cells much more sensitive to HHT treatment.
    Jingjing Xue, Peng Chu, Wenjuan Gao, Furong Wang, Yuan Gao, Shuqing Liu, Zhijie Kang, Jinsong Yan, Haina Wang.
      Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleophosmin (NPM1) mutation. Because 95% mutations give NPM1 an additional nuclear export signaling (NES) and dislocate NPM1 in cytoplasm (NPMc+), relocating NPM1 in nucleus provide an innovative strategy for treating this type of AML. The nuclear export of NPM1 depends on the nuclear protein export receptor XPO1, which recognizes the NES sequence on NPM1. Homoharringtonine (HHT) is a first-line chemotherapy drug of AML, yet the exact mechanism of its anti-AML activity is elusive. In this study, we found that HHT can directly target XPO1 to its NES-binding cleft, bind to Cys528 of XPO1, and inhibits its nuclear transport function. In addition, HHT can block NPMc+ proteins nuclear export and thus make NPMc+ AML cells much more sensitive to HHT treatment. Furthermore, the sensitivity of NPMc+ AML cells to HHT is a universal phenomenon irrespective of the different genetic lesions of AML. Taken together, our findings suggest that XPO1 is a new target of HHT and provide a novel strategy for NPMc+ AML treatment.
    Keywords:  AML; Homoharringtonine; NPM1; Nuclear export signal; XPO1
    DOI:  https://doi.org/10.1016/j.bbrc.2023.07.027
  22. PLoS One. 2023 ;18(7): e0289014
    The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study.
    Sohaib M Al-Khatib, Obada Ababneh, Hassann Abushukair, Nour Abdo, Laith N Al-Eitan.
      Acute myeloid leukemia (AML) is a malignancy of the myeloid cells due to the clonal and malignant proliferation of blast cells. The etiology of AML is complex and involves environmental and genetic factors. Such genetic aberrations include FLT3, DNMT3, IDH1, IDH2, NAT2, and WT. In this study, we analyzed the relationship between five, not previously studied in any Arab population, single nucleotide polymorphisms (SNPs) and the risk and overall survival of AML in Jordanian patients. The SNPs are NAT2 (rs1799930 and rs1799931), IDH1 (rs121913500), and IDH2 (rs121913502 and rs1057519736). A total number of 30 AML patients and 225 healthy controls were included in this study. Females comprised 50% (n = 15) and 65.3% (n = 147) of patients and controls, respectively. For AML patients (case group) Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues and from peripheral blood samples for the control subjects group. Genotyping of the genetic polymorphisms was conducted using a sequencing protocol. Our study indicates that NAT2 rs1799930 SNP had a statistically significant difference in genotype frequency between cases and controls (p = 0.023) while IDH mutations did not correlate with the risk and survival of AML in the Jordanian population. These results were also similar in the TCGA-LAML cohorts with the notable exception of the rare NAT2 mutation. A larger cohort study is needed to further investigate our results.
    DOI:  https://doi.org/10.1371/journal.pone.0289014
  23. Blood. 2023 Jul 19. pii: blood.2023020731. [Epub ahead of print]
    The role of the MDM2/p53 axis in anti-tumor immune responses.
    Tilman Brummer, Robert Zeiser.
      Mouse double minute 2 homolog (MDM2) is a negative regulator of the tumor suppressor p53 and often highly expressed in acute myeloid leukemia (AML) and different solid tumors. Inactivating mutations in TP53, the gene encoding for p53, confers an unfavorable prognosis in AML and increases the risk for relapse after allogeneic hematopoietic cell transplantation (allo-HCT). We review the concept that manipulation of MDM2 and p53 could enhance immunogenicity of AML and solid tumor cells. Additionally, we discuss the mechanisms by which MDM2 and p53 regulate MHC class I and II expression, transcription of dsRNA of endogenous retroviruses, interferon responses, IL-15 production and TRAIL-receptor 1 and 2 expression on malignant cells. The direct effects of MDM2-inhibition or MDM2 deletion in effector T cells are discussed in the context of cancer immunotherapy. The preclinical findings are connected to clinical studies using MDM2-inhibition to enhance anti-tumor immunity in patients. In aggregate, this review summarizes current evidence supporting the use of MDM2-inhibition to restore p53, as well as direct effects of MDM2-inhibition on T cells as an emerging concept for combined anti-tumor immunotherapy against hematological malignancies and beyond.
    DOI:  https://doi.org/10.1182/blood.2023020731
  24. Haematologica. 2023 Jul 20.
    Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia.
    Rabia Shahswar, Gernot Beutel, Razif Gabdoulline, Adrian Schwarzer, Arnold Kloos, Christian Koenecke, Michael Stadler, Gudrun Gohring, Yvonne Lisa Behrens, Zhixiong Li, Louisa-Kristin Dallmann, Piroska Klement, Catherin Albert, Martin Wichmann, Yasmine Alwie, Axel Benner, Maral Saadati, Arnold Ganser, Felicitas Thol, Michael Heuser.
      Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) with or without venetoclax in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLA-IDA treated patients (78% vs. 47%; P=0.001), while MRD was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eightyone percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation (alloHCT) or donor lymphocyte infusion (DLI) after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA and FLA-IDA treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing MRD negative remission in a high proportion of R/R AML patients.
    DOI:  https://doi.org/10.3324/haematol.2023.282912
  25. Am J Blood Res. 2023 ;13(3): 84-93
    Expression of long non-coding RNA UCA1 and its clinical relevance in paediatric acute myeloid leukemia.
    Christine Wilson, Diwakar Sharma, Priyanka Swaroop, Sachin Kumar, Sameer Bakhshi, Surender K Sharawat.
      The underlying mechanisms and clinical significance of long non-coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) is largely unknown in acute myeloid leukemia (AML). We aimed to study the expression of lncRNA UCA1, and its biological and clinical relevance in AML. Expression of lncRNA UCA1 was quantified in peripheral blood (PB) samples of children with de novo AML (n=69), post-induction, after achieving complete remission (CR) (n=8), and in patients who had relapsed (n=10). Additionally, two external cohorts were analysed i.e., TCGA-LAML dataset and Leukemia-MILE study. We also quantified expression in four different AML cell lines and analysed expression after cell differentiation. A consistent pattern of low UCA1 expression in AML was observed in our cohort of sixty-nine patients at baseline (P < 0.0001) and in the TCGA and Leukemia-MILE datasets. In patients who achieved remission, expression was comparable to healthy individuals, while relapsed patients interestingly had lower levels of UCA1 (P=0.0002). Furthermore, lncRNA UCA1 expression was significantly lower in AML cell lines (THP-1, P=0.0112; KG-1, P=0.0168; and HL-60, P=0.0112) and increased when THP-1 cells were differentiated (P=0.0001). In our AML patient cohort, lower expression was significantly associated with CR (P=0.043), however, the impact on survival (EFS and OS) was not significant. This is the first study wherein the lncRNA UCA1 expression was studied in various AML cell lines along with AML patients at baseline, remission and relapse. In conclusion, we found that UCA1 is significantly downregulated in AML compared to healthy individuals and mature differentiated cells.
    Keywords:  AML; UCA1; differentiation; long non-coding RNA; tumor suppressor gene
  26. Blood. 2023 Jul 19. pii: blood.2023019961. [Epub ahead of print]
    Escape from T-cell targeting immunotherapies in acute myeloid leukemia.
    Jayakumar Vadakekolathu, Sergio Rutella.
      Single-cell and spatial multimodal technologies have propelled discoveries of the solid tumor microenvironment (TME) molecular features and their correlation with clinical response and resistance to immunotherapy. Computational tools are incessantly being developed to characterize tumor-infiltrating immune cells and to model tumor immune escape. These advances have led to substantial research into T-cell hypofunctional states in the TME and their reinvigoration with T cell-targeting approaches, including checkpoint inhibitors (CPI). Until recently, we lacked a high-dimensional picture of the acute myeloid leukemia (AML) TME, including compositional and functional differences in immune cells between disease onset and post-chemotherapy or post-transplantation relapse, and the dynamic interplay between immune cells and AML blasts at various maturation stages. AML subgroups with heightened interferon (IFN)-g signaling were shown to derive clinical benefit from CD123 x CD3 bispecific DART molecules and CPI, whilst being less likely to respond to standard-of-care cytotoxic chemotherapy. In this Review, we first highlight recent progress into deciphering immune effector states in AML (including T-cell exhaustion and senescence), oncogenic signaling mechanisms that could reduce the susceptibility of AML cells to T cell-mediated killing and the dichotomous roles of type I and II IFN in anti-tumor immunity. In the second part, we discuss how this knowledge could be translated into opportunities to manipulate the AML TME with the aim to overcome resistance to CPI and other T-cell immunotherapies, building on recent success stories in the solid tumor field, and we provide an outlook for the future.
    DOI:  https://doi.org/10.1182/blood.2023019961
  27. Nucleic Acids Res. 2023 Jul 18. pii: gkad581. [Epub ahead of print]
    DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias.
    Mathias Boulanger, Mays Aqrouq, Denis Tempé, Chamseddine Kifagi, Marko Ristic, Dana Akl, Rawan Hallal, Aude Carusi, Ludovic Gabellier, Marion de Toledo, Jon-Otti Sigurdsson, Tony Kaoma, Charlotte Andrieu-Soler, Thierry Forné, Eric Soler, Yosr Hicheri, Elise Gueret, Laurent Vallar, Jesper V Olsen, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis.
      Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.
    DOI:  https://doi.org/10.1093/nar/gkad581
  28. Eur J Haematol. 2023 Jul 16.
    Chimeric antigen receptor T cells for acute myeloid leukemia.
    Viktor Fetsch, Robert Zeiser.
      The use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B-cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo-HCT) relying on polyclonal allo-reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T-cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T-cell induced toxicity against normal hematopoietic cells, lack of long-term CAR T-cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi-targeted CAR T cells, and gene-therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR-induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T-cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells.
    Keywords:  CAR T cells; acute myeloid leukemia; immune escape; multitargeted CAR T cells; myelotoxicity
    DOI:  https://doi.org/10.1111/ejh.14047
  29. Blood. 2023 Jul 21. pii: blood.2022019195. [Epub ahead of print]
    BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice.
    Xia Xiao, Yang Xu, Gillian A Moschetta, Yang Yu, Allison L Fisher, Víctor Manuel Alfaro-Magallanes, Shasta McMillen, Sydney Phillips, Chia-Yu Wang, Jan Christian, Jodie L Babitt.
      Hepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drive still regulate hepcidin in mice lacking either ligand or both. Here, we utilize mice with an inactivating Bmp5 mutation (Bmp5se), either alone or together with a global or endothelial Bmp6 knockout, to investigate the functional role of BMP5 in hepcidin and systemic iron homeostasis regulation. We show that Bmp5se mutant mice exhibit hepcidin deficiency at 10 days of age, blunted hepcidin induction to oral iron gavage, and mild liver iron loading when fed a low- or high-iron diet. Loss of 1 or 2 functional Bmp5 alleles also leads to more iron loading in Bmp6 heterozygous mice and more profound hemochromatosis in global or endothelial Bmp6 knockout mice. Moreover, double Bmp5 and Bmp6 mutant mice fail to induce hepcidin in response to chronic dietary iron loading. Finally, erythroferrone (ERFE) binds directly to BMP5 and inhibits BMP5 induction of hepcidin in vitro. Whereas erythropoietin (EPO) suppresses hepcidin in Bmp5se mutant mice, EPO fails to suppress hepcidin in double Bmp5 and Bmp6 mutant males. Together, these data demonstrate that BMP5 has a functional role in hepcidin and iron homeostasis regulation, particularly under conditions where BMP6 is limited.
    DOI:  https://doi.org/10.1182/blood.2022019195
  30. Mol Pharm. 2023 Jul 18.
    Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.
    Thao M Nguyen, Manasi Jambhrunkar, Sook S Wong, David M Ross, Paul Joyce, John W Finnie, Jim Manavis, Kristen Bremmell, Melissa R Pitman, Clive A Prestidge.
      Acute myeloid leukemia (AML) kills 75% of patients and represents a major clinical challenge with a need to improve on current treatment approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor, MP-A08, induces cell death in AML. However, limitations in MP-A08's "drug-like properties" (solubility, biodistribution, and potency) hinder its pathway to the clinic. This study demonstrates a liposome-based delivery system of MP-A08 that exhibits enhanced MP-A08 potency against AML cells. MP-A08-liposomes increased MP-A08 efficacy against patient AML cells (>140-fold) and significantly prolonged overall survival of mice with human AML disease (P = 0.03). The significant antileukemic property of MP-A08-liposomes could be attributed to its enhanced specificity, bioaccessibility, and delivery to the bone marrow, as demonstrated in the pharmacokinetic and biodistribution studies. Our findings indicate that MP-A08-liposomes have potential as a novel treatment for AML.
    Keywords:  acute myeloid leukemia; liposomal drug encapsulation; nanomedicine; sphingosine kinase 1
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00078
  31. Blood. 2023 Jul 20. 142(3): 306
    Clonal hematopoiesis in VEXAS syndrome.
      
    DOI:  https://doi.org/10.1182/blood.2023021371
  32. J Clin Invest. 2023 Jul 18. pii: e163325. [Epub ahead of print]
    SF3B1 mutation and ATM deletion co-drive leukemogenesis via centromeric R-loop dysregulation.
    Martina Cusan, Haifeng Shen, Bo Zhang, Aijun Liao, Lu Yang, Meiling Jin, Mike Fernandez, Prajish Iyer, Yiming Wu, Kevyn L Hart, Catherine Gutierrez, Sara Nik, Shondra M Pruett-Miller, Jeremy Stark, Esther A Obeng, Teresa V Bowman, Catherine J Wu, Ren-Jang Lin, Lili Wang.
      RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematological ma-lignancies. We previously reported that co-expression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harbor-ing chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromo-somal instability (CIN) remains unclear. Here, we demonstrate that SF3B1 mutation promotes centro-meric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromo-some segregation, altered spindle architecture and aneuploidy, which can be alleviated by removal of cen-R-loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlies augmentation of cen-R-loop as overexpression of the normal isoform, but not the altered form, mitigates mitotic stress in SF3B1 mutant cells. Our study underscores the critical role of novel splice variants in linking RNA splicing dysregulation and CIN, and highlights cen-R-loop augmen-tation as a key mechanism for leukemogenesis.
    Keywords:  Cancer; DNA repair; Oncology
    DOI:  https://doi.org/10.1172/JCI163325
  33. Mol Cell. 2023 Jul 12. pii: S1097-2765(23)00475-6. [Epub ahead of print]
    UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
    Jonathan M Tsai, Jacob D Aguirre, Yen-Der Li, Jared Brown, Vivian Focht, Lukas Kater, Georg Kempf, Brittany Sandoval, Stefan Schmitt, Justine C Rutter, Pius Galli, Colby R Sandate, Jevon A Cutler, Charles Zou, Katherine A Donovan, Ryan J Lumpkin, Simone Cavadini, Paul M C Park, Quinlan Sievers, Charlie Hatton, Elizabeth Ener, Brandon D Regalado, Micah T Sperling, Mikołaj Słabicki, Jeonghyeon Kim, Rebecca Zon, Zinan Zhang, Peter G Miller, Roger Belizaire, Adam S Sperling, Eric S Fischer, Rafael Irizarry, Scott A Armstrong, Nicolas H Thomä, Benjamin L Ebert.
      Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
    Keywords:  HECT-E3 ligases; nuclear receptors; protein degradation; structural biology; ubiquitin ligases
    DOI:  https://doi.org/10.1016/j.molcel.2023.06.028
  34. Nat Cell Biol. 2023 Jul 17.
    Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.
    Joey J Ghersi, Gabriel Baldissera, Jared Hintzen, Stephanie A Luff, Siyuan Cheng, Ivan Fan Xia, Christopher M Sturgeon, Stefania Nicoli.
      Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.
    DOI:  https://doi.org/10.1038/s41556-023-01187-9
  35. Blood Adv. 2023 Jul 21. pii: bloodadvances.2023010169. [Epub ahead of print]
    An in vitro model of human hematopoiesis identifies a regulatory role for the aryl hydrocarbon receptor.
    D M Isha Olive Khan, Peer W F Karmaus, Anthony Bach, Robert B Crawford, Norbert E Kaminski.
      In vitro models to study simultaneous development of different human immune cells and hematopoietic lineages are lacking. We identified and characterized, using single-cell methods, an in vitro stromal-cell free culture system of human hematopoietic stem and progenitor cell (HSPC) differentiation that allows concurrent development of multiple immune cell lineages. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor influencing many biological processes in diverse cell types. Using this in vitro model, we found that AHR activation by the highly specific AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), drives differentiation of human umbilical cord-blood derived CD34+ HSPCs towards monocytes and granulocytes with a significant decrease in lymphoid and megakaryocyte lineage specification that may lead to reduced immunocompetence. Through use of single-cell modalities, we also discovered for the first time, that AHR activation decreased in progenitor cells, at both transcriptomic and protein levels, the expression of BCL11A and IRF8 which are critical genes involved in hematopoietic lineage specification processes. Our in vitro model of hematopoiesis, coupled with single cell tools, therefore allows for a better understanding of the role played by AHR in modulating hematopoietic differentiation.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010169
  36. Nature. 2023 Jul 19.
    Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
    Yogesh Goyal, Gianna T Busch, Maalavika Pillai, Jingxin Li, Ryan H Boe, Emanuelle I Grody, Manoj Chelvanambi, Ian P Dardani, Benjamin Emert, Nicholas Bodkin, Jonas Braun, Dylan Fingerman, Amanpreet Kaur, Naveen Jain, Pavithran T Ravindran, Ian A Mellis, Karun Kiani, Gretchen M Alicea, Mitchell E Fane, Syeda Subia Ahmed, Haiyin Li, Yeqing Chen, Cedric Chai, Jessica Kaster, Russell G Witt, Rossana Lazcano, Davis R Ingram, Sarah B Johnson, Khalida Wani, Margaret C Dunagin, Alexander J Lazar, Ashani T Weeraratna, Jennifer A Wargo, Meenhard Herlyn, Arjun Raj.
      Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
    DOI:  https://doi.org/10.1038/s41586-023-06342-8
  37. Leuk Res. 2023 Jun 28. pii: S0145-2126(23)00611-2. [Epub ahead of print]132 107346
    FLAG based v/s Standard 3 + 7 induction therapy in treatment naïve Acute Myeloid Leukemia: Time to think "beyond anthracyclines".
    Mohd Rizwan Shaikh, Bhumika Singh, Rohan Halder, Reema Singh, Mohd Riyan Shaikh, Narendra Agarwal, Nitin Bansal, Rayaz Ahmed, Sumeet Prakash Mirgh, Dinesh Bhurani.
      Daunorubicin and Cytarabine (DA; 3 + 7) has been the standard frontline Acute Myeloid Leukemia (AML) induction regimen resulting in Complete Remission (CR) rates of 50-70%. It is associated with induction mortality of 15-30%. We report a comparative analysis of DA versus fludarabine, cytarabine, G-CSF (FLAG) + /- Venetoclax in resource constrained settings. We conducted a single center, retrospective analysis of 37 treatment naïve fit AML patients from May 2021 to December 2022 who received either standard DA regimen (Group 1) or FLAG + /- Venetoclax (Group 2). The median patient age was 36.6 years in DA arm (n = 18) as compared to 40.1 years in FLAG arm (n = 19). CR rates at day 28 were 55.5% in group 1 and 89.4% in group 2 (odds ratio [OR], 7.20; 95% confidence interval [CI], 1.274 -40.678; P = 0.012). Patients in FLAG based therapy arm had shorter duration of neutropenia (P = 0.003), fewer episodes of grade 3 febrile neutropenia (P = 0.0228), shorter duration of antibiotic therapy (P = 0.03), lesser need of 3rd line antibiotic therapy (P = 0.0228). Mortality rates were 16.6% (n = 3) in (group 1) and 0% (n = 0) in (group 2) (p = 0.105). Our analysis supports that FLAG based induction regimen is an effective and well-tolerated therapy in treatment naïve fit AML patients.
    Keywords:  7 + 3 Induction; AML; FLAG±Venetoclax; Treatment Naïve; Upfront Induction
    DOI:  https://doi.org/10.1016/j.leukres.2023.107346
  38. Blood Adv. 2023 Jul 19. pii: bloodadvances.2023009840. [Epub ahead of print]
    Early cessation of calcineurin inhibitors is feasible post haploidentical blood stem cell transplant-the ANZHIT-1 study.
    John Moore, Nada Hamad, David J Gottlieb, Ashish Bajel, David S Ritchie, David T Yeung, Matthew Greenwood, Duncan Purtill, Steven Tran, Ann Solterbeck, Donna Aarons, John Kwan.
      Haploidentical haematopoietic stem cell transplant (Haplo HSCT) using post -transplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective with multiple conditioning regimens making conclusions difficult. ANZHIT-1 was a phase II study conducted at six Australian allogeneic HSCT centres. The primary endpoints were disease free and overall survival at 2 years post HSCT. The reduced intensity regimen (RIC) was fludarabine, cyclophosphamide, 200cGy TBI and the myeloablative regimen (MAC) was IV fludarabine, busulfan. PTCy, MMF (to D35) and a calcineurin inhibitor (CNI) were used as GVHD prophylaxis. CNIs were weaned and ceased by D+120 in eligible patients at D60. Patients (n=78, 52M:26F) with various haematological malignancies were included in the study with a median follow up of 732 days (28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease free survival probability at two years was 67.5% (95% CI: 53.2-85.6) for MAC recipients and 68.3% (95% CI: 56.3-83.01) for RIC recipients. Transplant related mortality (TRM) at D100 and 1 year were 4.9% (95% CI: 1.6-15.3) and 17.9% (95% CI: 8.8-36.5) in the MAC group compared to 3.1% (95% CI: 0.8.1-12) and 11.6% (95% CI: 6-22.4) respectively in the RIC group. The median time for elective cessation of CNI was D142.5 (47-1255) with no excess cGVHD or mortality. Of the evaluable patients, 71.6% were off immunosuppression at 12 months post-transplant. This prospective Haplo HSCT trial utilising PTCY demonstrates encouraging survival rates whilst demonstrating that early CNI withdrawal is feasible and safe. Clinical Trial # ACTRN 12617000151336.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009840
  39. Br J Haematol. 2023 Jul 19.
    Histone demethylase PHF8 facilitates the development of chronic myeloid leukaemia by directly targeting BCR::ABL1.
    Huimin Feng, Yue Fu, Zelong Cui, Minran Zhou, Lu Zhang, Zhenxing Gao, Sai Ma, Chunyan Chen.
      Although tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukaemia (CML), TKI resistance remains a major challenge. Here, we demonstrated that plant homeodomain finger protein 8 (PHF8), a histone demethylase was aberrantly enriched in CML samples compared to healthy controls. PHF8 inhibited CML cell differentiation and promoted CML cell proliferation. Furthermore, the proliferation-inhibited function of PHF8-knockdown have stronger effect on imatinib mesylate (IM)-resistant CML cells. Mechanistically, we identified that PHF8 as a transcriptional modulator interacted with the promoter of the BCR::ABL1 fusion gene and alters the methylation levels of H3K9me1, H3K9me2 and H3K27me1, thereby promoting BCR::ABL1 transcription. Overall, our study suggests that targeting PHF8, which directly regulates BCR::ABL1 expression, is a useful therapeutic approach for CML.
    Keywords:  BCR-ABL; CML; PHF8; histone demethylase; imatinib mesylate resistance
    DOI:  https://doi.org/10.1111/bjh.18983
  40. Nat Commun. 2023 Jul 20. 14(1): 4378
    Computational analysis of peripheral blood smears detects disease-associated cytomorphologies.
    José Guilherme de Almeida, Emma Gudgin, Martin Besser, William G Dunn, Jonathan Cooper, Torsten Haferlach, George S Vassiliou, Moritz Gerstung.
      Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a group of blood cancers characterised by cytopenias, dysplasia of hematopoietic cells and blast expansion. Examination of peripheral blood slides (PBS) in MDS often reveals changes such as abnormal granulocyte lobulation or granularity and altered red blood cell (RBC) morphology; however, some of these features are shared with conditions such as haematinic deficiency anemias. Definitive diagnosis of MDS requires expert cytomorphology analysis of bone marrow smears and complementary information such as blood counts, karyotype and molecular genetics testing. Here, we present Haemorasis, a computational method that detects and characterizes white blood cells (WBC) and RBC in PBS. Applied to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia, and iron deficiency anemia), Haemorasis detected over half a million WBC and millions of RBC and characterized their morphology. These large sets of cell morphologies can be used in diagnosis and disease subtyping, while identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS. Additionally, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. By integrating cytomorphological features using machine learning, Haemorasis was able to distinguish SF3B1-mutant MDS from other MDS using cytomorphology and blood counts alone, with high predictive performance. We validate our findings externally, showing that they generalize to other centers and scanners. Collectively, our work reveals the potential for the large-scale incorporation of automated cytomorphology into routine diagnostic workflows.
    DOI:  https://doi.org/10.1038/s41467-023-39676-y
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