bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒10‒15
39 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia.
  2. STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.
  3. IL-1β-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes.
  4. Glasdigib fails to slay the hedgehog in pivotal AML trials.
  5. MDS/CMML from resource-limited region: Characteristics and comparison to tertiary reference European center.
  6. Fms-like tyrosine kinase 3 positive acute myeloid leukemia.
  7. Using machine learning to unravel the intricacy of acute myeloid leukemia.
  8. The FLT3N701K mutation causes clinical AML resistance to gilteritinib and triggers TKI sensitivity switch to quizartinib.
  9. Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis.
  10. E7820, an anti-cancer sulfonamide, degrades RBM39 in patients with splicing factor mutant myeloid malignancies: a phase II clinical trial.
  11. DROPLET DIGITAL PCR FOR ONCOGENIC KMT2A FUSION DETECTION.
  12. The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.
  13. TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited.
  14. Abnormal adipogenic signaling in the bone marrow mesenchymal stem cells contributes to supportive microenvironment for leukemia development.
  15. Co-op CARs for targeting acute myeloid leukemia.
  16. Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
  17. Recent advances in the application of induced pluripotent stem cell technology to the study of myeloid malignancies.
  18. CALR mutations possess unique prognostic relevance in myelofibrosis-before and after transplant.
  19. Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status.
  20. High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.
  21. Progenitor like cell type of an MLL-EDC4 fusion in acute myeloid leukemia.
  22. Differentiation Syndrome in Acute Leukemia: APL and Beyond.
  23. AML in the elderly-A global view.
  24. Prognostic Significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in Patients with Myelofibrosis: A Retrospective Study.
  25. How Nutrition Regulates Hematopoietic Stem Cell Features.
  26. Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
  27. An enhancer RNA recruits MLL1 to regulate transcription of Myb.
  28. Downregulation of stromal syntenin sustains AML development.
  29. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  30. Histone Modifications Dictate MLL Genomic Alterations in Leukemia.
  31. Letermovir prophylaxis for cytomegalovirus reactivation in allogeneic hematopoietic cell transplant recipients: Single center Canadian data.
  32. Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.
  33. Alquezar-Artieda N, Kuzilkova D, Roberts J, et al. Restored biosynthetic pathways induced by MSCs serve as rescue mechanism in leukemia cells after L-asparaginase therapy. Blood Adv. 2023;7(10):2228-2236.
  34. Potent Personalized Venetoclax Partners for Acute Myeloid Leukemia Identified by Ex Vivo Drug Screening.
  35. Targeting menin: a promising therapeutic strategy for susceptible acute leukemia subtypes.
  36. Dissolving Fusion Oncoprotein Condensates to Reverse Aberrant Gene Expression.
  37. Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.
  38. The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
  39. Anti-obesity drugs' side effects: what we know so far.
  1. Leukemia. 2023 Oct 13.
    Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia.
    Jan-Niklas Eckardt, Sebastian Stasik, Christoph Röllig, Andreas Petzold, Tim Sauer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H Brümmendorf, Ralph Naumann, Björn Steffen, Volker Kunzmann, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W Krause, Regina Herbst, Mathias Hänel, Maher Hanoun, Ulrich Kaiser, Martin Kaufmann, Zdenek Rácil, Jiri Mayer, Uta Oelschlägel, Wolfgang E Berdel, Gerhard Ehninger, Hubert Serve, Carsten Müller-Tidow, Uwe Platzbecker, Claudia D Baldus, Andreas Dahl, Johannes Schetelig, Martin Bornhäuser, Jan Moritz Middeke, Christian Thiede.
      Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.
    DOI:  https://doi.org/10.1038/s41375-023-02061-1
  2. Leukemia. 2023 Oct 10.
    STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.
    Jiaying Xie, Mengyao Sheng, Shaoqin Rong, Dan Zhou, Chao Wang, Wanling Wu, Jingru Huang, Yue Sun, Yin Wang, Pingyue Chen, Yushuang Wu, Yuanxian Wang, Lan Wang, Bo O Zhou, Xinxin Huang, Colum P Walsh, Stefan K Bohlander, Jian Huang, Xiaoqin Wang, Guo-Liang Xu, Hai Gao, Yuheng Shi.
      Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases.
    DOI:  https://doi.org/10.1038/s41375-023-02055-z
  3. bioRxiv. 2023 Sep 30. pii: 2023.09.28.560018. [Epub ahead of print]
    IL-1β-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes.
    Vera Adema, Irene Ganan-Gomez, Feiyang Ma, Juan Jose Rodriguez-Sevilla, Kelly Chien, Hui Yang, Natthakan Thongon, Rashmi Kanagal-Shamanna, Sanam Loghavi, Guillermo Montalban-Bravo, Danielle Hammond, Yiqian Gu, Roselyn Tan, Lin Tan, Philip Lorenzi, Gheath Al-Atrash, Karen Clise-Dwyer, Rafael Bejar, Matteo Pellegrini, Guillermo Garcia-Manero, Simona Colla.
      Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.
    DOI:  https://doi.org/10.1101/2023.09.28.560018
  4. Leukemia. 2023 Oct 10.
    Glasdigib fails to slay the hedgehog in pivotal AML trials.
    Charles A Schiffer.
      
    DOI:  https://doi.org/10.1038/s41375-023-02049-x
  5. Eur J Haematol. 2023 Oct 11.
    MDS/CMML from resource-limited region: Characteristics and comparison to tertiary reference European center.
    Anna Sevoyan, Arsène Mekinian, Fatiha Chermat, Lionel Adès, A Ivanyan, Pierre Fenaux, Yervand Hakobyan.
      INTRODUCTION: Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are clonal myeloid malignancies, characterized by bone marrow failure leading to cytopenias (and possible myeloproliferation for CMML) and a high propensity to evolve to Acute Myeloid Leukemia (AML).OBJECTIVE AND METHODS: The aim of our retrospective study was to evaluate the clinical and hematological features; the prevalence of MDS subtypes, R-IPSS, and the outcome of 106 Armenian MDS/CMML patients diagnosed over the 2008-2020 period in a single Armenian Hematology center and compare them to French MDS patients included in the GFM registry.
    RESULTS: Median age in the Armenian cohort was 64 years (range 19-84) and 55% were males. The main MDS subtypes were MDS-MLD (29.2%) and MDS-SLD (27.3%), the least frequent was del 5q (0.9%). By comparison, a higher prevalence of MDS-MLD, MDS-EB2, and MDS-RS was found in the French cohort. Armenian patients' cohort generally had poor access to standard MDS treatment and 42.3% of the patients were transfusion dependent. Overall survival, however, did not significantly differ between Armenian and French cohorts.
    CONCLUSION: Our study stresses issues regarding epidemiology, access to diagnosis, difficulties of risk stratification, and access to treatment.
    Keywords:  MDS classification; MDS treatment; myelodysplastyc syndrome incidence
    DOI:  https://doi.org/10.1111/ejh.14115
  6. Curr Opin Oncol. 2023 Nov 01. 35(6): 589-593
    Fms-like tyrosine kinase 3 positive acute myeloid leukemia.
    Alessandro Isidori, Giuseppe Visani, Felicetto Ferrara.
      PURPOSE OF REVIEW: Fms-like tyrosine kinase 3 (FLT3) mutations are common in newly diagnosed patients with acute myeloid leukemia (AML). They are associated with a high risk of relapse. The identification of FLT3 mutations has important implications for the management of AML. FLT3 inhibitors have shown improved outcomes in FLT3-positive AML when used as a single agent in the salvage setting. However, the combination of inhibitors and chemotherapy in the first-line setting is the real game changer in FLT3mutant AML. The introduction of these drugs has improved the prognosis of FLT3-mutant AML, but the development of resistance is common. There are still many unanswered questions about FLT3-mutant AML.RECENT FINDINGS: This article will analyze recent advances for FLT3-mutant AML, focusing on front-line therapy and post-transplant maintenance.
    SUMMARY: Novel drug combinations and strategies against FLT3 mutated AML are currently under investigation and will be the focus of future studies. The development of more selective and potent FLT3 inhibitors may further improve outcomes for patients with FLT3-positive AML. Monitoring minimal residual disease and overcoming resistance are key issues for the future.
    DOI:  https://doi.org/10.1097/CCO.0000000000000993
  7. Haematologica. 2023 Oct 12.
    Using machine learning to unravel the intricacy of acute myeloid leukemia.
    Luca Guarnera, Valeria Visconte.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284085
  8. Am J Hematol. 2023 Oct 10.
    The FLT3N701K mutation causes clinical AML resistance to gilteritinib and triggers TKI sensitivity switch to quizartinib.
    Sunil K Joshi, Janét Pittsenbarger, Vanessa E Kennedy, Cheryl A C Peretz, Alexander E Perl, Catherine C Smith, Jeffrey W Tyner, Brian J Druker, Elie Traer.
      
    DOI:  https://doi.org/10.1002/ajh.27096
  9. Nat Commun. 2023 Oct 12. 14(1): 6414
    Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis.
    Mattheus H E Wildschut, Julien Mena, Cyril Dördelmann, Marc van Oostrum, Benjamin D Hale, Jens Settelmeier, Yasmin Festl, Veronika Lysenko, Patrick M Schürch, Alexander Ring, Yannik Severin, Michael S Bader, Patrick G A Pedrioli, Sandra Goetze, Audrey van Drogen, Stefan Balabanov, Radek C Skoda, Massimo Lopes, Bernd Wollscheid, Alexandre P A Theocharides, Berend Snijder.
      Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
    DOI:  https://doi.org/10.1038/s41467-023-42101-z
  10. Leukemia. 2023 Oct 09.
    E7820, an anti-cancer sulfonamide, degrades RBM39 in patients with splicing factor mutant myeloid malignancies: a phase II clinical trial.
    Jan Philipp Bewersdorf, Maximilian Stahl, Justin Taylor, Xiaoli Mi, Namrata Sonia Chandhok, Justin Watts, Andriy Derkach, Mateusz Wysocki, Sydney X Lu, Jessie Bourcier, Simon J Hogg, Jahan Rahman, Sana Chaudhry, Tulasigeri M Totiger, Omar Abdel-Wahab, Eytan M Stein.
      
    DOI:  https://doi.org/10.1038/s41375-023-02050-4
  11. J Mol Diagn. 2023 Oct 07. pii: S1525-1578(23)00222-2. [Epub ahead of print]
    DROPLET DIGITAL PCR FOR ONCOGENIC KMT2A FUSION DETECTION.
    Andrew L Young, Hannah C Davis, Grant A Challen.
      Acute myeloid leukemia (AML) is an aggressive blood cancer diagnosed in ∼120,000 individuals worldwide each year. During treatment for AML, detecting residual disease is essential for prognostication and treatment decision-making. Currently, methods for detecting residual AML are limited to identifying ∼1:100-1:1,000 leukemic cells (morphology, DNA sequencing) or difficult to implement (flow cytometry). AML arising after chemotherapy or radiation exposure is termed therapy-related AML (t-AML) and is exceptionally aggressive and treatment resistant. T-AML is often driven by oncogenic fusions resulting from prior treatments that introduce double-strand DNA breaks. The most common t-AML-associated translocations affect the histone-lysine N-methyltransferase 2A (KMT2A). There are at least 80 known KMT2A fusion partners, but about 80% of fusions involve just five partners - AF9, AF6, AF4, ELL and ENL. Here we present a novel droplet digital PCR (ddPCR) assay targeting the most common KMT2A-rearrangements to enable detection of rare AML cells harboring these fusions. This assay was benchmarked in cells lines and patient samples harboring oncogenic KMT2A fusions and demonstrated a limit of detection of approximately 1:1,000,000 cells. Future application of this assay could improve disease detection and treatment decision-making for t-AML patients with KMT2A fusions and detect pre-malignant oncogenic fusions in at-risk individuals after chemotherapy exposure.
    DOI:  https://doi.org/10.1016/j.jmoldx.2023.09.006
  12. EMBO Mol Med. 2023 Oct 09. e17810
    The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.
    Daniela Magliulo, Matilde Simoni, Carolina Caserta, Cristina Fracassi, Serena Belluschi, Kety Giannetti, Raffaella Pini, Ettore Zapparoli, Stefano Beretta, Martina Uggè, Eleonora Draghi, Federico Rossari, Nadia Coltella, Cristina Tresoldi, Marco J Morelli, Raffaella Di Micco, Bernhard Gentner, Luca Vago, Rosa Bernardi.
      One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.
    Keywords:  AML; ATRA; HIF2α; differentiation therapy
    DOI:  https://doi.org/10.15252/emmm.202317810
  13. Cancers (Basel). 2023 Sep 30. pii: 4816. [Epub ahead of print]15(19):
    TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited.
    Dong-Yeop Shin.
      INTRODUCTION: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein's DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML.CLINICAL IMPLICATIONS: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents.
    CONCLUSIONS: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.
    Keywords:  TP53 mutation; acute myeloid leukemia
    DOI:  https://doi.org/10.3390/cancers15194816
  14. Cell Commun Signal. 2023 Oct 10. 21(1): 277
    Abnormal adipogenic signaling in the bone marrow mesenchymal stem cells contributes to supportive microenvironment for leukemia development.
    Rawan Sabbah, Sahar Saadi, Tal Shahar-Gabay, Shiran Gerassy, Shlomit Yehudai-Resheff, Tsila Zuckerman.
      BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological malignancy, associated with unfavorable patient outcome, primarily due to disease relapse. Mesenchymal stem cells (MSCs) residing in the bone marrow (BM) niche are the source of mesenchyma-derived subpopulations, including adipocytes, and osteocytes, that are critical for normal hematopoiesis. This study aimed to characterize BM-derived adipocyte/osteocyte fractions and their crosstalk with AML cells as a potential mechanism underlying leukemogenesis.METHODS: BM cell subpopulations derived from primary AML patients were evaluated using humanized ex-vivo and in-vivo models, established for this study. The models comprised AML blasts, normal hematopoietic stem and progenitor cells and mesenchymal stromal subpopulations. ELISA, FACS analysis, colony forming unit assay, whole exome sequencing and real-time qPCR were employed to assess the differentiation capacity, genetic status, gene expression and function of these cell fractions. To explore communication pathways between AML cells and BM subpopulations, levels of signaling mediators, including cytokines and chemokines, were measured using the ProcartaPlex multiplex immunoassay.
    RESULTS: The study revealed deficiencies in adipogenic/osteogenic differentiation of BM-MSCs derived from AML patients, with adipocytes directly promoting survival and clonogenicity of AML cells in-vitro. In whole exome sequencing of BM-MSC/stromal cells, the AHNAK2 gene, associated with the stimulation of adipocyte differentiation, was found to be mutated and significantly under-expressed, implying its abnormal function in AML. The evaluation of communication pathways between AML cells and BM subpopulations demonstrated pronounced alterations in the crosstalk between these cell fractions. This was reflected by significantly elevated levels of signaling mediators cytokines/chemokines, in AML-induced adipocytes/osteocytes compared to non-induced MSCs, indicating abnormal hematopoiesis. Furthermore, in-vivo experiments using a fully humanized 3D scaffold model, showed that AML-induced adipocytes were the dominant component of the tumor microenvironment, providing preferential support to leukemia cell survival and proliferation.
    CONCLUSIONS: This study has disclosed direct contribution of impaired functional, genetic and molecular properties of AML patient-derived adipocytes to effective protection of AML blasts from apoptosis and to stimulation of their growth in vitro and in vivo, which overall leads to disease propagation and relapse. The detected AHNAK2 gene mutations in AML-MSCs point to their involvement in the mechanism underlying abnormal adipogenesis. Video Abstract.
    Keywords:  Acute myeloid leukemia; Adipocytes; Bone marrow niche; Mesenchymal stem cells; Osteocytes
    DOI:  https://doi.org/10.1186/s12964-023-01231-z
  15. Cancer Cell. 2023 Oct 10. pii: S1535-6108(23)00348-3. [Epub ahead of print]
    Co-op CARs for targeting acute myeloid leukemia.
    Taisuke Kondo, Naomi Taylor.
      Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop an "IF-BETTER" strategy. Their combinatorial chimeric co-stimulatory receptor with an attenuated CAR enhances acute myeloid leukemia (AML) killing while protecting healthy progenitors, highlighting the potential to leverage cooperative CAR designs.
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.015
  16. Annu Rev Pathol. 2023 Oct 13.
    Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
    Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo.
      Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-051222-122724
  17. Adv Biol Regul. 2023 Sep 27. pii: S2212-4926(23)00039-8. [Epub ahead of print] 100993
    Recent advances in the application of induced pluripotent stem cell technology to the study of myeloid malignancies.
    Dharamveer Tatwavedi, Andrea Pellagatti, Jacqueline Boultwood.
      Acquired myeloid malignancies are a spectrum of clonal disorders known to be caused by sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells, leading to their aberrant self-renewal and differentiation. The increasing use of induced pluripotent stem cell (iPSC) technology to study myeloid malignancies has helped usher a paradigm shift in approaches to disease modeling and drug discovery, especially when combined with gene-editing technology. The process of reprogramming allows for the capture of the diversity of genetic lesions and mutational burden found in primary patient samples into individual stable iPSC lines. Patient-derived iPSC lines, owing to their self-renewal and differentiation capacity, can thus be a homogenous source of disease relevant material that allow for the study of disease pathogenesis using various functional read-outs. Furthermore, genome editing technologies like CRISPR/Cas9 enable the study of the stepwise progression from normal to malignant hematopoiesis through the introduction of specific driver mutations, individually or in combination, to create isogenic lines for comparison. In this review, we survey the current use of iPSCs to model acquired myeloid malignancies including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia and MDS/MPN overlap syndromes. The use of iPSCs has enabled the interrogation of the underlying mechanism of initiation and progression driving these diseases. It has also made drug testing, repurposing, and the discovery of novel therapies for these diseases possible in a high throughput setting.
    Keywords:  CRISPR/Cas9 gene editing; Drug screening; Gene mutations; Induced pluripotent stem cells; Myeloid malignancy; Reprogramming
    DOI:  https://doi.org/10.1016/j.jbior.2023.100993
  18. Bone Marrow Transplant. 2023 Oct 11.
    CALR mutations possess unique prognostic relevance in myelofibrosis-before and after transplant.
    Ayalew Tefferi, Alessandro M Vannucchi.
      
    DOI:  https://doi.org/10.1038/s41409-023-02112-2
  19. Cell Commun Signal. 2023 Oct 12. 21(1): 283
    Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status.
    Jirarat Poohadsuan, George A O'Doherty, Weerapat Owattanapanich, Smith Kungwankiattichai, Yon Rojanasakul, Surapol Issaragrisil, Sudjit Luanpitpong.
      BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by an accumulation of immature leukemic myeloblasts initiating from leukemic stem cells (LSCs)-the subpopulation that is also considered the root cause of chemotherapy resistance. Repurposing cardiac glycosides to treat cancers has gained increasing attention and supporting evidence, but how cardiac glycosides effectively target LSCs, e.g., whether it involves cell differentiation, remains largely unexplored.METHODS: Digoxin, a user-designed digitoxigenin-α-L-rhamnoside (D6-MA), and ouabain were tested against various human AML-derived cells with different maturation phenotypes. Herein, we established two study models to specifically determine the effects of cardiac glycosides on LSC death and differentiation-one allowed change in dynamics of LSCs and leukemic progenitor cells (LPCs), while another maintained their undifferentiated status. Regulatory mechanisms underlying cardiac glycoside-induced cytotoxicity were investigated and linked to cell cycle distribution and apoptotic machinery.
    RESULTS: Primitive AML cells containing CD34+ LSCs/LPCs were very responsive to nanomolar concentrations of cardiac glycosides, with ouabain showing the greatest efficiency. Ouabain preferentially induces caspase-dependent apoptosis in LSCs, independent of its cell differentiation status, as evidenced by (i) the tremendous induction of apoptosis by ouabain in AML cells that acquired less than 15% differentiation and (ii) the higher rate of apoptosis in enriched LSCs than in LPCs. We sorted LSCs and LPCs according to their cell cycle distribution into G0/G1, S, and G2/M cells and revealed that G0/G1 cells in LSCs, which was its major subpopulation, were the top ouabain responders, indicating that the difference in ouabain sensitivity between LSCs and LPCs involved both distinct cell cycle distribution and intrinsic apoptosis regulatory mechanisms. Further, Mcl-1 and c-Myc, which were differentially expressed in LSCs and LPCs, were found to be the key apoptosis mediators that determined ouabain sensitivity in AML cells. Ouabain induces a more rapid loss of Mcl-1 and c-Myc in LSCs than in LPCs via the mechanisms that in part involve an inhibition of Mcl-1 protein synthesis and an induction of c-Myc degradation.
    CONCLUSIONS: Our data provide new insight for repurposing cardiac glycosides for the treatment of relapsed/refractory AML through targeting LSCs via distinct cell cycle and apoptosis machinery. Video Abstract.
    Keywords:  Acute myeloid leukemia; Apoptosis; Cardiac glycosides; Cell cycle; Leukemic stem cell; Mcl-1; Ouabain; c-Myc
    DOI:  https://doi.org/10.1186/s12964-023-01317-8
  20. Onco Targets Ther. 2023 ;16 803-816
    High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.
    Michele Massimino, Stefania Stella, Elena Tirrò, Maria Stella Pennisi, Fabio Stagno, Silvia Rita Vitale, Chiara Romano, Cristina Tomarchio, Nunziatina Laura Parrinello, Livia Manzella, Francesco Di Raimondo, Paolo Vigneri.
      Purpose: Chronic Myeloid Leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by expression of the BCR::ABL1 oncoprotein. High BCR::ABL1 levels have been associated to proliferative advantage of leukemic cells, blast crisis progression and tyrosine kinase inhibitors (TKIs) inefficacy. We have previously shown that high BCR::ABL1/GUSIS transcripts measured at diagnosis are associated with inferior responses to standard dose Imatinib (IM). However, the mechanisms underlying the higher rates of disease progression and development of TKIs resistance dependent on elevated BCR::ABL1 levels remain unclear.Methods: Leukemic cells were collected from CML patients showing, at diagnosis, high or low BCR::ABL1/GUSIS. BCR::ABL1 expression levels were measured using real-time PCR. Short-term culture and long-term culture-initiating cells assays were employed to investigate the role of BCR::ABL1 gene-expression levels on proliferation, clonogenicity, signal transduction, TKIs responsiveness and self-renewal ability. Cell division was performed by carboxyfluorescein-succinimidyl ester (CFSE) assay.
    Results: We found that BCR::ABL1 oncogene expression levels correlate in both PMNs and CD34+ cells. Furthermore, high oncogene levels increased both proliferation and anti-apoptotic signaling via ERK and AKT phosphorylation. Moreover, high BCR::ABL1 expression reduced the clonogenicity of leukemic CD34+ cells and increased their sensitivity to high doses IM but not to those of dasatinib. Furthermore, we observed that high BCR::ABL1 levels are associated with a reduced self-renewal of primitive leukemic cells and, also, that these cells showed comparable TKIs responsiveness with cells expressing lower BCR::ABL1 levels. Interestingly, we found a direct correlation between high BCR::ABL1 levels and reduced number of quiescent leukemic cells caused by increasing their cycling.
    Conclusion: Higher BCR::ABL1 levels improving the proliferation, anti-apoptotic signaling and reducing self-renewal properties cause an increased expansion of leukemic clone.
    Keywords:  BCR:ABL1; CD34; LTC-IC; TKIs; self-renewal
    DOI:  https://doi.org/10.2147/OTT.S413825
  21. Blood Adv. 2023 Oct 11. pii: bloodadvances.2022009096. [Epub ahead of print]
    Progenitor like cell type of an MLL-EDC4 fusion in acute myeloid leukemia.
    Linda C Schuster, Afzal P Syed, Stephan M Tirier, Simon Steiger, Isabelle Seufert, Heiko Becker, Jesus Duque-Afonso, Tobias Ma, Seishi Ogawa, Jan-Philipp Mallm, Michael Lübbert, Karsten Rippe.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022009096
  22. Cancers (Basel). 2023 Sep 28. pii: 4767. [Epub ahead of print]15(19):
    Differentiation Syndrome in Acute Leukemia: APL and Beyond.
    Ashley C Woods, Kelly J Norsworthy.
      Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute promyelocytic leukemia (APL). DS was subsequently observed more broadly with targeted therapeutics for acute myeloid leukemia (AML). DS is typically characterized by fever, dyspnea, hypotension, weight gain, pleural or pericardial effusions, and acute renal failure. The incidence in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens. Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality. The targeted anti-leukemic therapy should be discontinued in patients with severe DS. Here, we discuss the pathogenesis of DS, clinical presentations, diagnostic criteria, management strategies, and implementation of prospective tracking on clinical trials.
    Keywords:  AML; APL; ATO; ATRA; differentiation syndrome
    DOI:  https://doi.org/10.3390/cancers15194767
  23. Br J Haematol. 2023 Oct 11.
    AML in the elderly-A global view.
    Peter Hokland, Isolda I Fernández, Sylvie D Freeman, Bjørn T Gjertsen, Jie Jin, Vidh Murthy, Masamitsu Yanada, Arnold Ganser.
      
    Keywords:  acute myeloid leukaemia; elderly; global view; leukaemia diagnosis; minimal residual disease
    DOI:  https://doi.org/10.1111/bjh.19135
  24. Cancers (Basel). 2023 Sep 24. pii: 4698. [Epub ahead of print]15(19):
    Prognostic Significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in Patients with Myelofibrosis: A Retrospective Study.
    Kira-Lee Koster, Nora-Medea Messerich, Thomas Volken, Sergio Cogliatti, Thomas Lehmann, Lukas Graf, Andreas Holbro, Rudolf Benz, Izadora Demmer, Wolfram Jochum, Tata Nageswara Rao, Tobias Silzle.
      In myelofibrosis, comorbidities (CMs) add prognostic information independently from the Dynamic International Prognostic Scoring System (DIPSS). The Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) offers a simple tool for CM assessment as it is calculable after having performed a careful history and physical examination, a small routine chemistry panel (including creatinine and liver enzymes) and a limited set of functional diagnostics. To assess the prognostic impact of the MDS-CI in addition to the DIPSS and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70, we performed a retrospective chart review of 70 MF patients who had not received allogeneic stem cell transplantation (primary MF, n = 51; secondary MF, n = 19; median follow-up, 40 months) diagnosed at our institution between 2000 and 2020. Cardiac diseases (23/70) and solid tumors (12/70) were the most common CMs observed at MF diagnosis. Overall survival (OS) was significantly influenced by the MDS-CI (median OS MDS-CI low (n = 38): 101 months; MDS-CI intermediate (n = 25): 50 months; and high (n = 7): 8 months; p < 0.001). The MDS-CI added prognostic information after inclusion as a categorical variable in a multivariate model together with the dichotomized DIPSS or the dichotomized MIPSS70: MDS-CI high HR 14.64 (95% CI 4.42; 48.48), p = 0.0002, and MDS-CI intermediate HR 1.97 (95% CI 0.96; 4.03), p = 0.065, and MDS-CI high HR 19.65 (95% CI 4.71; 81.95), p < 0.001, and MDS-CI intermediate HR 1.063 (95% CI 0.65; 4.06), p = 0.2961, respectively. The analysis of our small and retrospective MF cohort suggests that the MDS-CI represents a useful tool to identify MF patients with an increased vulnerability due to comorbidities. However, analyses of larger cohorts are necessary to define the value of the MDS-CI as a prognostic tool in comparison with other comorbidity indices.
    Keywords:  DIPSS; MDS-CI; MIPSS70; comorbidities; myelofibrosis; prognostic systems
    DOI:  https://doi.org/10.3390/cancers15194698
  25. Exp Hematol. 2023 Oct 08. pii: S0301-472X(23)01735-6. [Epub ahead of print]
    How Nutrition Regulates Hematopoietic Stem Cell Features.
    Katharina Schönberger, Nina Cabezas-Wallscheid.
      Our dietary choices significantly impact all the cells in our body. Increasing evidence suggests that diet-derived metabolites influence hematopoietic stem cell (HSC) metabolism and function, thereby actively modulating blood homeostasis. This is of particular relevance since regulating the metabolic activity of HSCs is crucial for maintaining stem cell fitness and mitigating the risk of hematological disorders. In this review, we examine the current scientific knowledge of the impact of the diet on stemness features, and we specifically highlight the established mechanisms by which dietary components modulate metabolic and transcriptional programs in adult HSCs. Gaining a deeper understanding of how nutrition influences our HSC compartment may pave the way for targeted dietary interventions with the potential to decelerate aging and improve the effectiveness of transplantation and cancer therapies.
    Keywords:  Diet; Metabolism; Stem Cells (hematopoietic stem cells)
    DOI:  https://doi.org/10.1016/j.exphem.2023.09.008
  26. bioRxiv. 2023 Sep 30. pii: 2023.09.30.560315. [Epub ahead of print]
    Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
    Anderson R Frank, Florentina Vandiver, David G McFadden.
      Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.
    DOI:  https://doi.org/10.1101/2023.09.30.560315
  27. bioRxiv. 2023 Sep 26. pii: 2023.09.26.559528. [Epub ahead of print]
    An enhancer RNA recruits MLL1 to regulate transcription of Myb.
    Juhyun Kim, Luis F Diaz, Matthew J Miller, Benjamin Leadem, Ivan Krivega, Ann Dean.
      The Myb proto-oncogene encodes the transcription factor c-MYB, which is critical for the proliferation and differentiation of hematopoietic stem and progenitor cells. Distant enhancers of Myb expression form a hub of interactions with the Myb promoter but the regulation of Myb during hematopoiesis is still incompletely understood. Here we identified a novel nuclear Myb long non-coding enhancer RNA ( Myrlin ) that originates from the -81 kb murine Myb enhancer within the Myb ─ Hbs1l intergenic region. Myrlin and Myb are coordinately regulated in a developmental stage-specific fashion during maturation of erythroid progenitors and upon differentiation of MEL cells. CRISPR/Cas9 genome editing of the Myrlin transcription start site at the -81kb enhancer reduced both Myrlin and Myb expression. Deletion of the Myrlin TSS reduced occupancy by the looping protein LDB1, compromising long-range hub contacts between the Myb promoter and its enhancer and reducing RNA Pol II occupancy across the Myb locus. In contrast, silencing of Myrlin using CRISPRi, while similarly reducing both Myrlin and Myb expression, left the Myb enhancer hub undisturbed, revealing that chromatin looping and transcription activation of Myb can be decoupled. Investigating a role for Myrlin , per se , we found that Myrlin interacts with MLL1 complex, a transcriptional coactivator that plays an essential role in regulating gene expression during hematopoiesis. Myrlin CRISPRi compromised MLL1 occupancy in the Myb locus and decreased CDK9 and RNA Pol II binding. Myrlin CRISPRi further resulted in pausing of RNA Pol II in the Myb first exon/intron. These data document that Myrlin directly participates in activating Myb transcription by recruiting MLL1.
    DOI:  https://doi.org/10.1101/2023.09.26.559528
  28. EMBO Mol Med. 2023 Oct 11. e17570
    Downregulation of stromal syntenin sustains AML development.
    Raphael Leblanc, Rania Ghossoub, Armelle Goubard, Rémy Castellano, Joanna Fares, Luc Camoin, Stephane Audebert, Marielle Balzano, Berna Bou-Tayeh, Cyril Fauriat, Norbert Vey, Sylvain Garciaz, Jean-Paul Borg, Yves Collette, Michel Aurrand-Lions, Guido David, Pascale Zimmermann.
      The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro-tumoral microenvironment. From serial transplantations in mice and co-culture experiments, we conclude that syntenin-deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro-tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML-stroma crosstalk and unsuspected tumor-suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.
    Keywords:  cell-to-cell communication; syntenin; tumor aggressiveness; tumor-stroma
    DOI:  https://doi.org/10.15252/emmm.202317570
  29. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  30. Cancer Discov. 2023 Oct 13. OF1
    Histone Modifications Dictate MLL Genomic Alterations in Leukemia.
      The balance of H3K9me1/2 at the MLL/KMT2A locus regulates MLL/KMT2A amplification/rearrangements seen in leukemia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-164
  31. Eur J Haematol. 2023 Oct 13.
    Letermovir prophylaxis for cytomegalovirus reactivation in allogeneic hematopoietic cell transplant recipients: Single center Canadian data.
    Ian Pang, Peggy Chen, Gertrude V Trinh, Mats Remberger, Igor Novitzky-Basso, Armin Gerbitz, Dennis D Kim, Rajat Kumar, Wilson Lam, Arjun D Law, Jeffrey H Lipton, Auro Viswabandya, Ivan Pasic, Jonas Mattsson, Fotios V Michelis.
      BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post-alloHCT outcomes.METHODS: We retrospectively examined 273 alloHCT recipients, 158 in the non-letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV-seropositive and met criteria for high risk of CMV reactivation.
    RESULTS: Median start of letermovir was 21 days post-alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p < .001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p = .54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p = .69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p = .27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR.
    CONCLUSIONS: Letermovir prophylaxis started at day +21 post-alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes.
    Keywords:  allogeneic stem cell transplantation; cytomegalovirus; letermovir; outcomes; prophylaxis
    DOI:  https://doi.org/10.1111/ejh.14117
  32. Cell Chem Biol. 2023 Oct 10. pii: S2451-9456(23)00332-X. [Epub ahead of print]
    Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.
    Debanjan Bhattacharjee, Jaweria Bakar, Surbhi P Chitnis, Erin L Sausville, Kumar Dilip Ashtekar, Brianna E Mendelson, Kaitlin Long, Joan C Smith, David E Heppner, Jason M Sheltzer.
      The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.
    Keywords:  EGFR; cancer; drug targeting; mechanism of action; pharmacogenomics
    DOI:  https://doi.org/10.1016/j.chembiol.2023.09.013
  33. Blood Adv. 2023 Oct 24. 7(20): 6023
    Alquezar-Artieda N, Kuzilkova D, Roberts J, et al. Restored biosynthetic pathways induced by MSCs serve as rescue mechanism in leukemia cells after L-asparaginase therapy. Blood Adv. 2023;7(10):2228-2236.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023011150
  34. Blood Cancer Discov. 2023 Oct 12. OF1-OF3
    Potent Personalized Venetoclax Partners for Acute Myeloid Leukemia Identified by Ex Vivo Drug Screening.
    Pamela S Becker.
      SUMMARY: High-throughput screens (HTS) have been utilized to assess the efficacy of single drugs against patient tumor samples with the purpose of optimizing precision therapy, but testing the synergy of drug combinations can identify the ideal second drug to add. With novel sophisticated HTS, effective venetoclax combinations can be revealed that provide the cell state, phenotype, and molecular features of the susceptible and resistant cell populations. See related article by Eide et al. (14) .
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0180
  35. Signal Transduct Target Ther. 2023 Oct 11. 8(1): 384
    Targeting menin: a promising therapeutic strategy for susceptible acute leukemia subtypes.
    Pietro Di Fazio.
      
    DOI:  https://doi.org/10.1038/s41392-023-01627-w
  36. Cancer Res. 2023 Oct 13. 83(20): 3324-3326
    Dissolving Fusion Oncoprotein Condensates to Reverse Aberrant Gene Expression.
    Hazheen K Shirnekhi, Bappaditya Chandra, Richard W Kriwacki.
      In a recent study, Wang and colleagues reported that a significant fraction of cancer-associated fusion proteins display a common structural topology, including an N-terminal phase separation-prone region (PS) from one parent protein and a C-terminal DNA-binding domain (DBD) from the other. This is reminiscent of the structural topology of transcription factors and led to the hypothesis that the PS-DBD fusions form aberrant transcriptional condensates through phase separation, which was supported through transcriptomic data analysis and cellular condensate assays. The authors developed a high-throughput screen based upon time-lapse, high-content imaging to identify 114 compounds that dissolved condensates formed by a chromatin-dissociated mutant of FUS::ERG (FUS::ERGmut). One of these compounds, LY2835219, was shown to dissolve FUS::ERGmut condensates by promoting lysosome formation and was also active against condensates formed by other PS-DBD fusions, including EWS::FLI1. Finally, condensate dissolution by LY2835219 was shown to reverse aberrant gene expression driven by EWS::FLI1, although how this compound specifically marshals lysosomes to target some PS-DBD fusions and not other condensate-forming proteins remains elusive. This work not only highlights likely roles for aberrant condensate formation in the oncogenic function of PS-DBD fusions, but also provides proof of principle for mechanistically unbiased screening to identify compounds that modulate fusion protein-driven condensates and their oncogenic functions.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2769
  37. Acta Haematol. 2023 Oct 12.
    Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.
    Lia Minculescu, Joanne Reekie, Soeren Lykke Petersen, Brian Thomas Kornblit, Ida Schjoedt, Niels Smedegaard Andersen, Lisbeth Pernille Andersen, Anne Fischer-Nielsen, Eva Kannik Haastrup, Lone Smidstrup Friis, Henrik Sengelov.
      INTRODUCTION: Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here we report results of DLI/Azacitidine treatment from a retrospective single-center study.METHODS: 50 AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine.
    RESULTS: Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI+low-dose-Azacitidine group, 5-years relapse-free survival was 40%.
    CONCLUSION: DLI remains an effective treatment in post-transplant relapse leaving one fifth of patients long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes.
    DOI:  https://doi.org/10.1159/000534315
  38. Exp Hematol. 2023 Oct 11. pii: S0301-472X(23)01736-8. [Epub ahead of print]
    The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
    Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) have the properties to self-renew and/or differentiate into all mature blood cell lineages. The fate decisions to generate progeny that retain stemness properties or that commit to differentiation is a fundamental process to maintain tissue homeostasis and must be tightly regulated in order to prevent HSC overgrowth or exhaustion. HSC fate decisions are inherently coupled to cell division. The transition from quiescence to activation is accompanied by major metabolic and mitochondrial changes that are important for cell cycle entry for balanced decisions between self-renewal and differentiation. In this review, we discuss the current understanding of the role of mitochondrial metabolism in HSC transition from quiescence to activation and fate decisions.
    DOI:  https://doi.org/10.1016/j.exphem.2023.10.001
  39. Nature. 2023 Oct 13.
    Anti-obesity drugs' side effects: what we know so far.
    Mariana Lenharo.
      
    Keywords:  Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-023-03183-3
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