bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–09–10
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.
  2. Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower-intensity therapy: Roadmap from an ELN-DAVID expert panel.
  3. Persistent IDH mutations are not associated with increased relapse or death in patients with IDH -mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.
  4. The role of anti-thymocyte globulin in allogeneic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD) for secondary AML in remission: a study from the ALWP /EBMT.
  5. Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia - implications for the European leukemia net risk classification.
  6. FUS-ERG induces late-onset azacitidine resistance in acute myeloid leukaemia cells.
  7. Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
  8. Targeting apoptosis dysregulation in myeloid malignancies - The promise of a therapeutic revolution.
  9. Allogeneic hematopoietic cell transplantation in patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT.
  10. Clinical status of induction therapy incorporating a hypomethylating agent for newly diagnosed adult acute myeloid leukemia compared to the standard 7+3 regimen.
  11. CAR virus receptor mediates erythroid differentiation and migration and is downregulated in MDS.
  12. Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution.
  13. Should we move to a genomic classification of neutrophilic myeloid neoplasms?
  14. Abbreviated venetoclax with decitabine or azacitidine in acute myeloid leukemia.
  15. Spi1 R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice.
  16. Gemtuzumab ozogamicin plus standard induction hemotherapy improves outcomes of newly diagnosed intermediate cytogenetic risk acute myeloid leukemia.
  17. Acute myeloid leukemia with mutated TP53: Is this newly proposed entity oversimplifying a complex group of neoplasms?
  18. PRL2 inhibition elevates PTEN protein and ameliorates progression of Acute Myeloid Leukemia.
  19. Vitamin C and D Supplementation in Acute Myeloid Leukemia.
  20. PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.
  21. Baseline correlates of frailty and its association with survival in United States veterans with acute myeloid leukemia.
  22. Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.
  23. CRISPR-ChIP reveals selective regulation of H3K79me2 by Menin in MLL leukemia.
  24. Location, location, location: A mini-review of CEBPA variants in patients with acute myeloid leukemia.
  25. Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.
  26. PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia.
  27. Genotoxic effects of base and prime editing in human hematopoietic stem cells.
  28. Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation.
  29. eIF3d controls the persistent integrated stress response.
  30. Functional and molecular profiling of hematopoietic stem cells during regeneration.
  31. CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them.
  1. Am J Hematol. 2023 Sep 04.
    Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.
    Alex Bataller, Sanam Loghavi, Yoheved Gerstein, Alexandre Bazinet, Koji Sasaki, Kelly S Chien, Danielle Hammond, Guillermo Montalban-Bravo, Gautam Borthakur, Nicholas Short, Ghayas C Issa, Tapan M Kadia, Naval Daver, Guilin Tang, Andres Quesada, Keyur P Patel, Farhad Ravandi, Warren Fiskus, Cristopher P Mill, Hagop M Kantarjian, Kapil Bhalla, Guillermo Garcia-Manero, Betul Oran, Courtney D DiNardo.
      DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.
    DOI:  https://doi.org/10.1002/ajh.27070
  2. Am J Hematol. 2023 Sep 06.
    Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower-intensity therapy: Roadmap from an ELN-DAVID expert panel.
    Farhad Ravandi, Jacqueline Cloos, Francesco Buccisano, Richard Dillon, Konstanze Döhner, Sylvie D Freeman, Christopher S Hourigan, Gerrit J Ossenkoppele, Gail J Roboz, Marion Subklewe, Christian Thiede, Isabell Arnhardt, Peter J M Valk, Adriano Venditti, Andrew H Wei, Roland B Walter, Michael Heuser.
      With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with intensive chemotherapy to refine prognosis and, possibly, inform treatment decision-making, its value in the context of lower-intensity regimens is unclear. As such regimens have gained in popularity and can be associated with higher response rates, the need to better define the role of MRD assessment and the appropriate time points and assays used for this purpose has increased. This report outlines a roadmap for MRD testing in patients with AML treated with lower-intensity regimens. Experts from the European LeukemiaNet (ELN)-DAVID AML MRD working group reviewed all available data to propose a framework for MRD testing in future trials and clinical practice. A Delphi poll served to optimize consensus. Establishment of uniform standards for MRD assessments in lower-intensity regimens used in treating patients with AML is clinically relevant and important for optimizing testing and, ultimately, improving treatment outcomes of these patients.
    DOI:  https://doi.org/10.1002/ajh.27087
  3. medRxiv. 2023 Aug 21. pii: 2023.08.14.23294087. [Epub ahead of print]
    Persistent IDH mutations are not associated with increased relapse or death in patients with IDH -mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.
    Niveditha Ravindra, Laura W Dillon, Gege Gui, Matthew Smith, Lukasz P Gondek, Richard J Jones, Adam Corner, Christopher S Hourigan, Alexander J Ambinder.
      The presence of measurable residual disease (MRD) prior to an allogeneic hematopoietic transplant (alloHCT) in Acute Myeloid Leukemia (AML) has been shown to be associated with an increased risk of post-transplant relapse. Since the Isocitrate Dehydrogenase genes ( IDH1 / 2 ) are mutated in a considerable proportion of patients with AML, we studied if these mutations would serve as useful targets for MRD. Fifty-five IDH -mutated AML patients undergoing non-myeloablative alloHCT with post-transplant cyclophosphamide at a single center were sequenced at baseline using a multi-gene panel followed by targeted testing for persistent IDH mutations at the pre- and post-alloHCT timepoints by digital droplet PCR or error-corrected next generation sequencing. The cohort included patients who had been treated with IDH inhibitors pre- and post-transplant (20% and 17% for IDH1 and 38% and 28% for IDH2 ). Overall, 55% of patients analyzed had detectable IDH mutations during complete remission prior to alloHCT. However, there were no statistically significant differences in overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR) at 3 years between patients who tested positive or negative for a persistent IDH mutation during remission (OS: IDH1 p=1, IDH2 p=0.87; RFS: IDH1 p=0.71, IDH2 p= 0.78; CIR: IDH1 p=0.92, IDH2 p=0.97). There was also no difference in the prevalence of persistent IDH mutation between patients who did and did not receive an IDH inhibitor (p=0.59). Mutational profiling of available relapse samples showed that 8 out of 9 patients still exhibited the original IDH mutation, indicating that the IDH mutations remained stable through the course of the disease. This study demonstrates that persistent IDH mutations during remission is not associated with inferior clinical outcomes after alloHCT in patients with AML.
    DOI:  https://doi.org/10.1101/2023.08.14.23294087
  4. Bone Marrow Transplant. 2023 Sep 02.
    The role of anti-thymocyte globulin in allogeneic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD) for secondary AML in remission: a study from the ALWP /EBMT.
    Arnon Nagler, Myriam Labopin, Nicolaus Kröger, Thomas Schroeder, Tobias Gedde-Dahl, Matthias Eder, Georg-Nikolaus Franke, Igor Wolfgang Blau, Urpu Salmenniemi, Gerard Socie, Johannes Schetelig, Matthias Stelljes, Fabio Ciceri, Mohamad Mohty.
      We compared outcomes, of 1609 patients with secondary acute myeloid leukemia (sAML) undergoing allogeneic transplantation (HSCT) in first complete remission (CR1) from matched unrelated donors (MUD) from 2010 to 2021, receiving or not receiving anti-thymocyte globulin (ATG) (ATG-1308, no ATG-301). Median age was 60.9 (range, 18.5-77.8) and 61.1 (range, 21.8-75.7) years, (p = 0.3). Graft versus host disease (GVHD) prophylaxis was cyclosporin-A with methotrexate (41%) or mycophenolate mofetil (38.2%), without significant differences between groups. Day 28, engraftment (ANC > 0.5 × 109/L) was 92.3% vs 95.3% (p = 0.17), respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD (p = 0.002 and p = 0.015), total and extensive chronic GVHD (p = 0.008 and p < 0.0001), and relapse incidence (RI) (p = 0.039), while non-relapse mortality (NRM) did not differ (p = 0.51). Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95, p = 0.014) and HR = 0.68 (95% CI 0.57-0.8, p < 0.0001), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1, p = 0.051). The main causes of death were the original disease, infection, and GVHD. In conclusion, ATG reduces GVHD and improves LFS, OS, and GRFS in sAML patients without increasing the RI, despite sAML being a high-risk disease.
    DOI:  https://doi.org/10.1038/s41409-023-02095-0
  5. Leukemia. 2023 Sep 07.
    Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia - implications for the European leukemia net risk classification.
    Jan-Niklas Eckardt, Marius Bill, Christian Rausch, Klaus Metzeler, Karsten Spiekermann, Sebastian Stasik, Tim Sauer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H Brümmendorf, Utz Krug, Bernhard Wörmann, Wolfgang Hiddemann, Dennis Görlich, Cristina Sauerland, Björn Steffen, Hermann Einsele, Andreas Neubauer, Andreas Burchert, Kerstin Schäfer-Eckart, Wolfgang E Berdel, Christoph Schliemann, Stefan W Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Leo Ruhnke, Johannes Schetelig, Jan Moritz Middeke, Hubert Serve, Claudia D Baldus, Uwe Platzbecker, Carsten Müller-Tidow, Martin Bornhäuser, Tobias Herold, Christian Thiede, Christoph Röllig.
      
    DOI:  https://doi.org/10.1038/s41375-023-02016-6
  6. Sci Rep. 2023 09 02. 13(1): 14454
    FUS-ERG induces late-onset azacitidine resistance in acute myeloid leukaemia cells.
    Ai Asai-Nishishita, Masahiro Kawahara, Goichi Tatsumi, Masaki Iwasa, Aya Fujishiro, Rie Nishimura, Hitoshi Minamiguchi, Katsuyuki Kito, Makoto Murata, Akira Andoh.
      FUS-ERG is a chimeric gene with a poor prognosis, found in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). It remains unclear whether DNA hypomethylating agents, including azacitidine (Aza), are effective in FUS-ERG-harbouring AML and how FUS-ERG induces chemoresistance. Stable Ba/F3 transfectants with FUS-ERG were repeatedly exposed to Aza for 7 days of treatment and at 21-day intervals to investigate Aza sensitivity. Stable FUS-ERG transfectants acquired resistance acquired resistance after three courses of Aza exposure. RNA sequencing (RNA-seq) was performed when Aza susceptibility began to change; genes with altered expression or transcript variants were identified. Molecular signatures of these genes were analysed using gene ontology. RNA-seq analyses identified 74 upregulated and 320 downregulated genes involved in cell motility, cytokine production, and kinase activity. Additionally, 1321 genes with altered transcript variants were identified, revealing their involvement in chromatin organisation. In a clinical case of AML with FUS-ERG, we compared whole-genome alterations between the initial MDS diagnosis and AML recurrence after Aza treatment. Genes with non-synonymous or near mutations in transcription regulatory areas (TRAs), additionally detected in AML recurrence, were collated with the gene list from RNA-seq to identify genes involved in acquiring Aza resistance in the presence of FUS-ERG. Whole-genome sequencing of clinical specimens identified 29 genes with non-synonymous mutations, including BCOR, and 48 genes located within 20 kb of 54 TRA mutations in AML recurrence. These genes were involved in chromatin organisation and included NCOR2 as an overlapping gene with RNA-seq data. Transcription regulators involved in mutated TRAs were skewed and included RCOR1 in AML recurrence. We tested the efficacy of BH3 mimetics, including venetoclax and S63845, in primary Aza-resistant AML cells treated with FUS-ERG. Primary FUS-ERG-harbouring AML cells acquiring Aza resistance affected the myeloid cell leukaemia-1 (MCL1) inhibitor S63845 but not while using venetoclax, despite no mutations in BCL2. FUS-ERG promoted Aza resistance after several treatments. The disturbance of chromatin organisation might induce this by co-repressors, including BCOR, NCOR2, and RCOR1. MCL1 inhibition could partially overcome Aza resistance in FUS-ERG-harbouring AML cells.
    DOI:  https://doi.org/10.1038/s41598-023-41230-1
  7. Nat Commun. 2023 Sep 08. 14(1): 5536
    Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
    Derek W Brown, Liam D Cato, Yajie Zhao, Satish K Nandakumar, Erik L Bao, Eugene J Gardner, Aubrey K Hubbard, Alexander DePaulis, Thomas Rehling, Lei Song, Kai Yu, Stephen J Chanock, John R B Perry, Vijay G Sankaran, Mitchell J Machiela.
      Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.
    DOI:  https://doi.org/10.1038/s41467-023-41315-5
  8. Blood Rev. 2023 Aug 29. pii: S0268-960X(23)00091-7. [Epub ahead of print] 101130
    Targeting apoptosis dysregulation in myeloid malignancies - The promise of a therapeutic revolution.
    Enrico Santinelli, Maria Rosaria Pascale, Zhuoer Xie, Talha Badar, Maximilian F Stahl, Jan P Bewersdorf, Carmelo Gurnari, Amer M Zeidan.
      In recent years, the therapeutic landscape of myeloid malignancies has been completely revolutionized by the introduction of several new drugs, targeting molecular alterations or pathways crucial for leukemia cells survival. Particularly, many agents targeting apoptosis have been investigated in both pre-clinical and clinical studies. For instance, venetoclax, a pro-apoptotic agent active on BCL-2 signaling, has been successfully used in the treatment of acute myeloid leukemia (AML). The impressive results achieved in this context have made the apoptotic pathway an attractive target also in other myeloid neoplasms, translating the experience of AML. Therefore, several drugs are now under investigation either as single or in combination strategies, due to their synergistic efficacy and capacity to overcome resistance. In this paper, we will review the mechanisms of apoptosis and the specific drugs currently used and under investigation for the treatment of myeloid neoplasia, identifying critical research necessities for the upcoming years.
    Keywords:  Apoptosis; Myeloid neoplasia; Therapeutic vulnerability; Venetoclax
    DOI:  https://doi.org/10.1016/j.blre.2023.101130
  9. Bone Marrow Transplant. 2023 Sep 07.
    Allogeneic hematopoietic cell transplantation in patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT.
    Juan Carlos Hernández-Boluda, Diderik-Jan Eikema, Linda Koster, Nicolaus Kröger, Marie Robin, Moniek de Witte, Jürgen Finke, Maria Chiara Finazzi, Annoek Broers, Ludek Raida, Nicolaas Schaap, Patrizia Chiusolo, Mareike Verbeek, Carin L E Hazenberg, Kazimierz Halaburda, Aleksandr Kulagin, Hélène Labussière-Wallet, Tobias Gedde-Dahl, Werner Rabitsch, Kavita Raj, Joanna Drozd-Sokolowska, Giorgia Battipaglia, Nicola Polverelli, Tomasz Czerw, Ibrahim Yakoub-Agha, Donal P McLornan.
      Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALR mutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF.
    DOI:  https://doi.org/10.1038/s41409-023-02094-1
  10. Expert Rev Hematol. 2023 Sep 08. 1-11
    Clinical status of induction therapy incorporating a hypomethylating agent for newly diagnosed adult acute myeloid leukemia compared to the standard 7+3 regimen.
    Akihiro Ohmoto, Shigeo Fuji.
       INTRODUCTION: Cytarabine and anthracycline combination therapy (7 + 3 regimen) is the standard care for induction chemotherapy in adult patients with acute myeloid leukemia (AML). Although this intensive regimen achieves a high response rate, it is highly toxic, especially in elderly or frail patients. Hypomethylating agents approved initially for high-risk myelodysplastic syndrome had longer survival times than conventional care in elderly patients with newly diagnosed AML.
    AREAS COVERED: We summarize the latest information regarding induction therapy using hypomethylating agents (azacitidine and decitabine) for newly diagnosed AML.
    EXPERT OPINION: For untreated patients ineligible for an intensive regimen, a phase III trial exhibited the survival benefit of adding the highly selective BCL2 inhibitor venetoclax to azacitidine. The National Comprehensive Cancer Network guidelines recommend azacitidine or decitabine plus venetoclax as an option for patients with poor-risk AML, including those with TP53 mutations and AML with the cytogenetic features of myelodysplastic syndrome. Future studies should evaluate positioning this combination as an induction therapy for younger patients eligible for hematopoietic stem cell transplantation. Without randomized trials, propensity score matching analysis suggested a comparable prognosis between azacitidine combination and intensive chemotherapy. Considering the feasibility of a doublet regimen incorporating azacitidine, a triplet regimen should be examined.
    Keywords:  Azacitidine; decitabine; induction chemotherapy; standard 7+3 regimen; venetoclax
    DOI:  https://doi.org/10.1080/17474086.2023.2256472
  11. Leukemia. 2023 Sep 06.
    CAR virus receptor mediates erythroid differentiation and migration and is downregulated in MDS.
    Karin Bauer, Sigrid Machherndl-Spandl, Lukas Kazianka, Irina Sadovnik, Sinan Gültekin, Susanne Suessner, Johannes Proell, Jeroen Lauf, Gregor Hoermann, Gregor Eisenwort, Norman Häfner, Mathilde Födermayr-Mayrleitner, Ann-Sofie Schmolke, Emiel van der Kouwe, Uwe Platzbecker, Thomas Lion, Ansgar Weltermann, Otto Zach, Gerald Webersinke, Ulrich Germing, Christian Gabriel, Wolfgang R Sperr, Marie C Béné, Philipp B Staber, Peter Bettelheim, Peter Valent.
      Myelodysplastic syndromes (MDS) are myeloid neoplasms presenting with dysplasia in the bone marrow (BM) and peripheral cytopenia. In most patients anemia develops. We screened for genes that are expressed abnormally in erythroid progenitor cells (EP) and contribute to the pathogenesis of MDS. We found that the Coxsackie-Adenovirus receptor (CAR = CXADR) is markedly downregulated in CD45low/CD105+ EP in MDS patients compared to control EP. Correspondingly, the erythroblast cell lines HEL, K562, and KU812 stained negative for CAR. Lentiviral transduction of the full-length CXADR gene into these cells resulted in an increased expression of early erythroid antigens, including CD36, CD71, and glycophorin A. In addition, CXADR-transduction resulted in an increased migration against a serum protein gradient, whereas truncated CXADR variants did not induce expression of erythroid antigens or migration. Furthermore, conditional knock-out of Cxadr in C57BL/6 mice resulted in anemia and erythroid dysplasia. Finally, decreased CAR expression on EP was found to correlate with high-risk MDS and decreased survival. Together, CAR is a functionally relevant marker that is down-regulated on EP in MDS and is of prognostic significance. Decreased CAR expression may contribute to the maturation defect and altered migration of EP and thus their pathologic accumulation in the BM in MDS.
    DOI:  https://doi.org/10.1038/s41375-023-02015-7
  12. Nat Genet. 2023 Sep;55(9): 1531-1541
    Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution.
    Alba Rodriguez-Meira, Ruggiero Norfo, Sean Wen, Agathe L Chédeville, Haseeb Rahman, Jennifer O'Sullivan, Guanlin Wang, Eleni Louka, Warren W Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean-Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Daniela Moralli, Lamia Subha Meem, Joana Carrelha, Bishan Wu, Angela Hamblin, Helene Guermouche, Florence Pasquier, Christophe Marzac, François Girodon, William Vainchenker, Mark Drummond, Claire Harrison, J Ross Chapman, Isabelle Plo, Sten Eirik W Jacobsen, Bethan Psaila, Supat Thongjuea, Iléana Antony-Debré, Adam J Mead.
      Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.
    DOI:  https://doi.org/10.1038/s41588-023-01480-1
  13. Blood Adv. 2023 Sep 06. pii: bloodadvances.2023011103. [Epub ahead of print]
    Should we move to a genomic classification of neutrophilic myeloid neoplasms?
    Gonzalo Carreño-Tarragona, Alberto Álvarez-Larrán, Juan Carlos Hernández-Boluda, Rosa Ayala, Nicholas Cp Cross.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023011103
  14. Leuk Res. 2023 Aug 16. pii: S0145-2126(23)00635-5. [Epub ahead of print]134 107370
    Abbreviated venetoclax with decitabine or azacitidine in acute myeloid leukemia.
    Ian M Bouligny, Graeme Murray, Thuy Ho, Michael Doyel, Tilak Patel, Josh Boron, Valerie Tran, Juhi Gor, Yiwei Hang, Yanal Alnimer, Kyle Zacholski, Chad Venn, Nolan A Wages, Steven Grant, Keri R Maher.
      
    Keywords:  AML; Hypomethylating agent; IDH1; IDH2; Toxicity; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2023.107370
  15. iScience. 2023 Sep 15. 26(9): 107530
    Spi1 R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice.
    Natalie Brown, Rosemary Finnon, Paul Finnon, Roisin McCarron, Lourdes Cruz-Garcia, Grainne O'Brien, Eleanor Herbert, Cheryl L Scudamore, Edouard Morel, Christophe Badie.
      Ionizing radiation (IR) is a risk factor for acute myeloid leukemia (rAML). Murine rAMLs feature both hemizygous chromosome 2 deletions (Del2) and point mutations (R235) within the hematopoietic regulatory gene Spi1. We generated a heterozygous CBA Spi1 R235 mouse (CBASpm/+) which develops de novo AML with 100% incidence by ∼12 months old and shows a dose-dependent reduction in latency following X-irradiation. These effects are reduced on an AML-resistant C57Bl6 genetic background. CBASpm/Gfp reporter mice show increased Gfp expression, indicating compensation for Spm-induced Spi1 haploinsufficiency. Del2 is always detected in both de novo and rAMLs, indicating that biallelic Spi1 mutation is required for AML. CBASpm/+ mice show that a single Spm modification is sufficient for initiating AML development with complete penetrance, via the "two-hit" mechanism and this is accelerated by IR exposure. Similar SPI1/PU.1 polymorphisms in humans could potentially lead to enhanced susceptibility to IR following medical or environmental exposure.
    Keywords:  Cancer; Genetics; Molecular Genetics
    DOI:  https://doi.org/10.1016/j.isci.2023.107530
  16. Blood Cancer J. 2023 Sep 04. 13(1): 131
    Gemtuzumab ozogamicin plus standard induction hemotherapy improves outcomes of newly diagnosed intermediate cytogenetic risk acute myeloid leukemia.
    Hassan Awada, Mina Abdelmalek, Tara Cronin, Jeffrey Baron, Zakariya Kashour, Farhan Azad, Muhammad Salman Faisal, Mark Faber, Matthew Gravina, Pamela J Sung, Steven D Green, Amanda Przespolewski, James E Thompson, Elizabeth A Griffiths, Eunice S Wang.
      
    DOI:  https://doi.org/10.1038/s41408-023-00910-x
  17. Am J Hematol. 2023 Sep 08.
    Acute myeloid leukemia with mutated TP53: Is this newly proposed entity oversimplifying a complex group of neoplasms?
    Hong Fang, L Jeffery Medeiros, Wei Wang.
      
    DOI:  https://doi.org/10.1002/ajh.27085
  18. JCI Insight. 2023 Sep 04. pii: e170065. [Epub ahead of print]
    PRL2 inhibition elevates PTEN protein and ameliorates progression of Acute Myeloid Leukemia.
    Colin Carlock, Yunpeng Bai, Allison Paige-Hood, Qinglin Li, Frederick Nguele Meke, Zhong-Yin Zhang.
      Overexpression of Phosphatases of Regenerating Liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation, and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in Acute Myeloid Leukemia (AML) patients. In the current study, a PTEN-knockdown AML animal model was generated to assess the impact of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the bone marrow niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN, and downregulation of AKT/mTOR regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.
    Keywords:  Hematology; Leukemias; Phosphoprotein phosphatases; Therapeutics; Tumor suppressors
    DOI:  https://doi.org/10.1172/jci.insight.170065
  19. Blood Adv. 2023 Sep 06. pii: bloodadvances.2023010559. [Epub ahead of print]
    Vitamin C and D Supplementation in Acute Myeloid Leukemia.
    Pierre Luc Mouchel, Emilie Bérard, Suzanne Tavitian, Noémie Gadaud, Francois Vergez, Jean Baptiste Rieu, Isabelle Luquet, Audrey Sarry, Françoise Huguet, Laetitia Largeaud, Eric Delabesse, Anne Huynh, Sarah Bertoli, Christian Récher.
      Recent studies have highlighted the role of vitamin C and D in AML. In 2018, we changed our practices to add both vitamins to the supportive care for all consecutive AML patients undergoing intensive chemotherapy. In this study, we compared the outcomes of patients treated before and after this change in practice. From 2015 to 2020, 431 patients were included, 262 of whom received no supplementation and 169 of whom received vitamin supplementation. Vitamin C and vitamin D was administered from day 10 of chemotherapy until hematologic recovery from induction and consolidation. Most patients presented at diagnosis with low levels of vitamin C and D. Upon recovery from induction, vitamin D levels among the vit C/D group significantly increased compared to diagnosis, and pre-transplant levels were significantly higher in the vit C/D group compared to the control group (median of 33 vs. 19 ng/mL; P<0.0001). During induction, the rates of bacterial or fungal infection, hemorrhage, or macrophage activation syndrome were lower in the vit C/D group, whereas there was no difference in response rate, relapse incidence, and OS. However, the multivariate analysis for OS showed a significant interaction between vitamin C/D and NPM1 mutation, meaning that vitamin C/D supplementation was significantly and independently associated with better OS in patients with NPM1 mutations (HR 0.52; 95% CI: 0.30-0.90; P=0.019) compared to wild-type NPM1 patients (HR 1.01; 95% CI: 0.68-1.51; P=0.95). In conclusion, vitamin C/D supplementation is safe and could influence the outcomes of AML patients undergoing intensive chemotherapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010559
  20. Cell Rep Med. 2023 Sep 04. pii: S2666-3791(23)00358-0. [Epub ahead of print] 101191
    PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.
    Bruktawit Maru, Alessandra Messikommer, Linhui Huang, Katja Seipel, Olivia Kovecses, Peter J M Valk, Alexandre P A Theocharides, Francois E Mercier, Thomas Pabst, Maureen McKeague, Nathan W Luedtke.
      Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses.
    Keywords:  NAD+ ADP-ribosyltransferase 1; PAR; PARP-1; acute myelomonocytic and monocytic leukemia; apoptosis; cancer biology; caspase-independent programmed cell death; nucleoside analog; poly(ADP-ribose); precision medicine; prognostic blood test
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101191
  21. Leuk Lymphoma. 2023 Sep 06. 1-10
    Baseline correlates of frailty and its association with survival in United States veterans with acute myeloid leukemia.
    Jennifer La, Michelle H Lee, Mary T Brophy, Nhan V Do, Jane A Driver, David P Tuck, Nathanael R Fillmore, Clark Dumontier.
      Frailty is an important construct to measure in acute myeloid leukemia (AML). We used the Veterans Affairs Frailty Index (VA-FI) - calculated using readily available data within the VA's electronic health records - to measure frailty in U.S. veterans with AML. Of the 1166 newly diagnosed and treated veterans with AML between 2012 and 2022, 722 (62%) veterans with AML were classified as frail (VA-FI > 0.2). At a median follow-up of 252.5 days, moderate-severely frail veterans had significantly worse survival than mildly frail, and non-frail veterans (median survival 179 vs. 306 vs. 417 days, p < .001). Increasing VA-FI severity was associated with higher mortality. A model with VA-FI in addition to the European LeukemiaNet (ELN) risk classification and other covariates statistically outperformed a model containing the ELN risk and other covariates alone (p < .001). These findings support the VA-FI as a tool to expand frailty measurement in research and clinical practice for informing prognosis in veterans with AML.
    Keywords:  Acute myeloid leukemia; electronic frailty index; frailty; geriatric oncology; overall survival; veterans
    DOI:  https://doi.org/10.1080/10428194.2023.2254434
  22. Sci Rep. 2023 Sep 08. 13(1): 14809
    Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.
    R F Schlenk, D Weber, J Krzykalla, T Kindler, G Wulf, B Hertenstein, H R Salih, T Südhoff, J Krauter, U Martens, S Wessendorf, V Runde, H J Tischler, M Bentz, E Koller, M Heuser, F Thol, A Benner, A Ganser, K Döhner, H Döhner.
      The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8-28; the dose of ATRA was reduced to 45 mg/m2, days 8-10 and 15 mg/m2, days 11-28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1-7 and etoposide 100 mg/day, p.o. or i.v., days 1-3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64-92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).
    DOI:  https://doi.org/10.1038/s41598-023-41964-y
  23. Nat Struct Mol Biol. 2023 Sep 07.
    CRISPR-ChIP reveals selective regulation of H3K79me2 by Menin in MLL leukemia.
    Omer Gilan, Laure Talarmain, Charles C Bell, Daniel Neville, Kathy Knezevic, Daniel T Ferguson, Marion Boudes, Yih-Chih Chan, Chen Davidovich, Enid Y N Lam, Mark A Dawson.
      Chromatin regulation involves the selective recruitment of chromatin factors to facilitate DNA repair, replication and transcription. Here we demonstrate the utility of coupling unbiased functional genomics with chromatin immunoprecipitation (CRISPR-ChIP) to identify the factors associated with active chromatin modifications in mammalian cells. Specifically, an integrated reporter containing a cis-regulatory element of interest and a single guide RNA provide a chromatinized template for a direct readout for regulators of histone modifications associated with actively transcribed genes such as H3K4me3 and H3K79me2. With CRISPR-ChIP, we identify all the nonredundant COMPASS complex members required for H3K4me3 and demonstrate that RNA polymerase II is dispensable for the maintenance of H3K4me3. As H3K79me2 has a putative oncogenic function in leukemia cells driven by MLL translocations, using CRISPR-ChIP we reveal a functional partitioning of H3K79 methylation into two distinct regulatory units: an oncogenic DOT1L complex directed by the MLL fusion protein in a Menin-dependent manner and a separate endogenous DOT1L complex, where catalytic activity is directed by MLLT10. Overall, CRISPR-ChIP provides a powerful tool for the unbiased interrogation of the mechanisms underpinning chromatin regulation.
    DOI:  https://doi.org/10.1038/s41594-023-01087-4
  24. Leuk Res Rep. 2023 ;20 100386
    Location, location, location: A mini-review of CEBPA variants in patients with acute myeloid leukemia.
    Muhammad Salman Faisal, Pamela J Sung.
      CEBPA variants are frequently recurring in acute myeloid leukemia (AML). The prognostic significance of CEBPA mutations has recently undergone a major shift in the 5th edition of WHO classification of hematological neoplasms and ELN 2022 classification. Whereas prior iterations did not specify the type of CEBPA mutation, the updated schema specify that only mutations localized to the C-terminal basic zipper (bZIP) domain are considered prognostically favorable. This change is based primarily on three recently published large datasets evaluating the prognostic significance of mutation location in CEBPA mutant AML. Here, we review the evolution of the prognostic classification of CEBPA variants.
    Keywords:  AML; BZIP; Biallelic; Monoallelic; Prognosis
    DOI:  https://doi.org/10.1016/j.lrr.2023.100386
  25. bioRxiv. 2023 Aug 26. pii: 2023.08.24.554523. [Epub ahead of print]
    Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.
    Tyler F Hill, Parnal Narvekar, Gregory Asher, Nathan Camp, Kerri R Thomas, Sarah K Tasian, David J Rawlings, Richard G James.
      Bispecific antibodies are an important tool for the management and treatment of acute leukemias. Advances in genome-engineering have enabled the generation of human plasma cells that secrete therapeutic proteins and are capable of long-term in vivo engraftment in humanized mouse models. As a next step towards clinical translation of engineered plasma cells (ePCs) towards cancer therapy, here we describe approaches for the expression and secretion of bispecific antibodies by human plasma cells. We show that human ePCs expressing either fragment crystallizable domain deficient anti-CD19 x anti-CD3 (blinatumomab) or anti-CD33 x anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of specific primary human cell subsets and B-acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro . We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19 bispecific secretion by ePCs and prevents self-targeting. Further, anti-CD19 bispecific-ePCs elicited tumor eradication in vivo following local delivery in flank-implanted Raji lymphoma cells. Finally, immunodeficient mice engrafted with anti-CD19 bispecific-ePCs and autologous T cells potently prevented in vivo growth of CD19 + acute lymphoblastic leukemia in patient-derived xenografts. Collectively, these findings support further development of ePCs for use as a durable, local delivery system for the treatment of acute leukemias, and potentially other cancers.
    Key points: Using gene editing, we engineered human plasma cells that secrete functional bispecifics to target leukemia cells expressing CD19 or CD33Engineered plasma cells secreting bispecifics suppress patient-derived leukemia in immunodeficient mice.
    DOI:  https://doi.org/10.1101/2023.08.24.554523
  26. Blood Cancer J. 2023 Sep 07. 13(1): 139
    PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia.
    Kinjal Shah, Ahmad Nasimian, Mehreen Ahmed, Lina Al Ashiri, Linn Denison, Wondossen Sime, Katerina Bendak, Iryna Kolosenko, Valentina Siino, Fredrik Levander, Caroline Palm-Apergi, Ramin Massoumi, Richard B Lock, Julhash U Kazi.
      The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism.
    DOI:  https://doi.org/10.1038/s41408-023-00914-7
  27. Nat Biotechnol. 2023 Sep 07.
    Genotoxic effects of base and prime editing in human hematopoietic stem cells.
    Martina Fiumara, Samuele Ferrari, Attya Omer-Javed, Stefano Beretta, Luisa Albano, Daniele Canarutto, Angelica Varesi, Chiara Gaddoni, Chiara Brombin, Federica Cugnata, Erika Zonari, Matteo Maria Naldini, Matteo Barcella, Bernhard Gentner, Ivan Merelli, Luigi Naldini.
      Base and prime editors (BEs and PEs) may provide more precise genetic engineering than nuclease-based approaches because they bypass the dependence on DNA double-strand breaks. However, little is known about their cellular responses and genotoxicity. Here, we compared state-of-the-art BEs and PEs and Cas9 in human hematopoietic stem and progenitor cells with respect to editing efficiency, cytotoxicity, transcriptomic changes and on-target and genome-wide genotoxicity. BEs and PEs induced detrimental transcriptional responses that reduced editing efficiency and hematopoietic repopulation in xenotransplants and also generated DNA double-strand breaks and genotoxic byproducts, including deletions and translocations, at a lower frequency than Cas9. These effects were strongest for cytidine BEs due to suboptimal inhibition of base excision repair and were mitigated by tailoring delivery timing and editor expression through optimized mRNA design. However, BEs altered the mutational landscape of hematopoietic stem and progenitor cells across the genome by increasing the load and relative proportions of nucleotide variants. These findings raise concerns about the genotoxicity of BEs and PEs and warrant further investigation in view of their clinical application.
    DOI:  https://doi.org/10.1038/s41587-023-01915-4
  28. J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02232-9. [Epub ahead of print] 105204
    Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation.
    Kevin E W Namitz, Scott A Showalter, Michael S Cosgrove.
      Enzymes that regulate the degree of histone H3 lysine 4 (H3K4) methylation are crucial for proper cellular differentiation and are frequently mutated in cancer. The Mixed Lineage leukemia (MLL) family of enzymes deposit H3K4 mono- di- or trimethylation at distinct genomic locations, requiring precise spatial and temporal control. Despite evidence that the degree of H3K4 methylation is controlled in part by a hierarchical assembly pathway with key subcomplex components, we previously found that the assembled state of the MLL1 core complex is not favored at physiological temperature. To better understand this paradox, we tested the hypothesis that increasing the concentration of subunits in a biomolecular condensate overcomes this thermodynamic barrier via mass action. Here we demonstrate that MLL1 core complex phase separation stimulates enzymatic activity up to 60-fold, but not primarily by concentrating subunits into droplets. Instead, we found that stimulated activity is largely due to formation of an altered oligomeric scaffold that greatly reduces substrate Km. We posit that phase separation induced scaffolding of the MLL1 core complex is a potential "switch-like" mechanism for spatiotemporal control of H3K4 methylation through the rapid formation or dissolution of biomolecular condensates within RNA Pol II transcription factories.
    Keywords:  NMR spectroscopy; analytical ultracentrifugation; enzyme kinetics; histone methylation; phase separation
    DOI:  https://doi.org/10.1016/j.jbc.2023.105204
  29. Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]
    eIF3d controls the persistent integrated stress response.
    Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.
      Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.
    Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
  30. Exp Hematol. 2023 Sep 02. pii: S0301-472X(23)01700-9. [Epub ahead of print]
    Functional and molecular profiling of hematopoietic stem cells during regeneration.
    Anna Rydström, Tan Hm Grahn, Abhishek Niroula, Els Mansell, Mark van der Garde, Maroulio Pertesi, Agatheeswaran Subramaniam, Shamit Soneji, Roman Zubarev, Tariq Enver, Björn Nilsson, Kenichi Miharada, Jonas Larsson, Stefan Karlsson.
      Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. While mouse HSCs have been well studied during homeostatic conditions, the mechanisms regulating HSC activation during stress remain unclear. Here, we analyzed the different phases of regeneration following transplantation. We isolated bone marrow from mice at eight time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs and the progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.
    DOI:  https://doi.org/10.1016/j.exphem.2023.08.010
  31. Hemasphere. 2023 Sep;7(9): e937
    CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them.
    Jolien Vanhooren, Rani Dobbelaere, Charlotte Derpoorter, Larissa Deneweth, Laurens Van Camp, Anne Uyttebroeck, Barbara De Moerloose, Tim Lammens.
      Conventional therapies for acute myeloid leukemia (AML) are characterized by high rates of relapse, severe toxicities, and poor overall survival rates. Thus, the development of new therapeutic strategies is crucial for improving the survival and quality of life of AML patients. CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy has been extremely successful in the treatment of B-cell acute lymphoid leukemia and several mature B-cell lymphomas. However, the use of CAR T-cell therapy for AML is currently prevented due to the lack of a myeloid equivalent to CD19, as currently known cell surface targets on leukemic blasts are also expressed on healthy hematopoietic stem and progenitor cells as well as their progeny. In addition, the immunosuppressive tumor microenvironment has a dampening effect on the antitumor activity of CAR-T cells. Here, we review the therapeutic challenges limiting the use of CAR T-cell therapy for AML and discuss promising novel strategies to overcome them.
    DOI:  https://doi.org/10.1097/HS9.0000000000000937
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