bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–03–19
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. C/EBPβ cooperates with MYB to maintain the oncogenic program of AML cells.
  2. Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines.
  3. Augmenting Venetoclax Activity Through Signal Transduction in AML.
  4. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.
  5. Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model.
  6. FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.
  7. Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin-beta receptor signaling.
  8. MEN1 mutations mediate clinical resistance to menin inhibition.
  9. Mdm2/p53 levels in bone marrow mesenchymal stromal cells is essential for maintaining the hematopoietic niche in response to DNA damage.
  10. Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.
  11. A multimodal analysis of genomic and RNA splicing features in myeloid malignancies.
  12. TP53 mutations are associated with increased infections and reduced hematopoietic cell transplantation rates in myelodysplastic syndrome and acute myeloid leukemia.
  13. The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial.
  14. Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells.
  15. Cytarabine-induced destabilization of MCL1 mRNA and protein triggers apoptosis in leukemia cells.
  16. Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.
  17. Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia.
  18. Platelet function studies in myeloproliferative neoplasms patients with Calreticulin or JAK2 V617F mutation.
  19. Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia.
  20. Differential effects of recombinant human thrombopoietin on clinical outcomes in CD7-positive and CD7-negative acute myeloid leukaemia.
  21. Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes.
  22. Explainable AI identifies diagnostic cells of genetic AML subtypes.
  23. Pharmacotherapeutic advances for splenomegaly in myelofibrosis.
  24. Magrolimab plus Azacitidine Is Safe and Efficacious in High-Risk MDS.
  25. MDM2 and BCL-2: to p53 or not to p53?
  26. Correction to "Recommendations for laboratory testing of UK patients with acute myeloid leukaemia".
  27. Artificial intelligence to empower diagnosis of myelodysplastic syndromes by multiparametric flow cytometry.
  28. Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms.
  29. Lactate regulates cell cycle by remodeling the anaphase promoting complex.
  30. Iron homeostasis governs erythroid phenotype in Polycythemia Vera.
  31. Whole-genome doubling drives oncogenic loss of chromatin segregation.
  32. Single-cell dissection of human hematopoietic reconstitution after allogeneic hematopoietic stem cell transplantation.
  1. Oncotarget. 2023 Mar 11. 14 174-177
    C/EBPβ cooperates with MYB to maintain the oncogenic program of AML cells.
    Karl-Heinz Klempnauer.
      Studies on the role of transcription factor MYB in acute myeloid leukemia (AML) have identified MYB as a key regulator of a transcriptional program for self-renewal of AML cells. Recent work summarized here has now highlighted the CCAAT-box/enhancer binding protein beta (C/EBPβ) as an essential factor and potential therapeutic target that cooperates with MYB and coactivator p300 in the maintenance of the leukemic cells.
    Keywords:  AML; C/EBPbeta; GFI1; MYB; p300
    DOI:  https://doi.org/10.18632/oncotarget.28377
  2. Leuk Res. 2023 Mar 03. pii: S0145-2126(23)00039-5. [Epub ahead of print]128 107054
    Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines.
    Raveen Stephen Stallon Illangeswaran, Daniel Zechariah Paul Jebanesan, Kezia Kanimozhi Sivakumar, Rakhi Thalayattu Vidhyadharan, Bharathi M Rajamani, Nancy Beryl Janet, Ernest David, Shaji Ramachandran Velayudhan, Vikram Mathews, Poonkuzhali Balasubramanian.
      Chemotherapy resistance leading to disease relapse is a significant barrier in treating acute myeloid leukemia (AML). Metabolic adaptations have been shown to contribute to therapy resistance. However, little is known about whether specific therapies cause specific metabolic changes. We established cytarabine-resistant (AraC-R) and Arsenic trioxide-resistant (ATO-R) AML cell lines, displaying distinct cell surface expression and cytogenetic abnormalities. Transcriptomic analysis revealed a significant difference in the expression profiles of ATO-R and AraC-R cells. Geneset enrichment analysis showed AraC-R cells rely on OXPHOS, while ATO-R cells on glycolysis. ATO-R cells were also enriched for stemness gene signatures, whereas AraC-R cells were not. The mito stress and glycolytic stress tests confirmed these findings. The distinct metabolic adaptation of AraC-R cells increased sensitivity to the OXPHOS inhibitor venetoclax. Cytarabine resistance was circumvented in AraC-R cells by combining Ven and AraC. In vivo, ATO-R cells showed increased repopulating potential, leading to aggressive leukemia compared to the parental and AraC-R. Overall, our study shows that different therapies can cause different metabolic changes and that these metabolic dependencies can be used to target chemotherapy-resistant AML.
    Keywords:  AML; Acquired chemoresistance; FLT3-ITD; Metabolic adaptation
    DOI:  https://doi.org/10.1016/j.leukres.2023.107054
  3. J Cell Signal. 2023 ;4(1): 1-12
    Augmenting Venetoclax Activity Through Signal Transduction in AML.
    Ian Michael Bouligny, Keri Renee Maher, Steven Grant.
      Venetoclax, a small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, selectively eradicates leukemic stem cells (LSCs). While venetoclax has revolutionized the treatment of acute myeloid leukemia (AML), treatment failure and disease relapse are common. Mechanisms underlying venetoclax resistance are surprisingly heterogeneous. Venetoclax resistance encompasses a spectrum of genetic and epigenetic changes, with numerous pathways contributing to the upregulation of additional anti-apoptotic proteins. In this review, we address the mechanisms of venetoclax resistance in the context of signal transduction. We emphasize how aberrant cell signaling impairs apoptosis and predisposes to venetoclax failure. Commonly activated pathways, such as FLT3, PI3K/AKT/mTOR, and RAS, contribute to upregulated anti-apoptotic mediators and are frequently responsible for refractory disease or disease relapse. We highlight novel combination strategies aimed at disabling constitutively active signal transduction to augment response and overcome venetoclax resistance.
    Keywords:  Acute myeloid leukemia; Akt pathway; Apoptotic pathways; B-cell lymphoma 2; FMS-like tyrosine kinase 3; Isocitrate dehydrogenase 1; Isocitrate dehydrogenase 2; MAPK pathway cell signaling; Signal transduction cascades
    DOI:  https://doi.org/10.33696/signaling.4.085
  4. Nature. 2023 Mar 15.
    The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.
    Ghayas C Issa, Ibrahim Aldoss, John DiPersio, Branko Cuglievan, Richard Stone, Martha Arellano, Michael J Thirman, Manish R Patel, David S Dickens, Shalini Shenoy, Neerav Shukla, Hagop Kantarjian, Scott A Armstrong, Florian Perner, Jennifer A Perry, Galit Rosen, Rebecca G Bagley, Michael L Meyers, Peter Ordentlich, Yu Gu, Vinit Kumar, Steven Smith, Gerard M McGeehan, Eytan M Stein.
      Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
    DOI:  https://doi.org/10.1038/s41586-023-05812-3
  5. Int J Biol Sci. 2023 ;19(4): 1211-1227
    Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model.
    Zhao Yin, Rui Su, Lanlan Ge, Xiuyuan Wang, Juhua Yang, Guiping Huang, Chuting Li, Yanjun Liu, Keda Zhang, Lan Deng, Jia Fei.
      BCR-ABL oncogene-mediated Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) is suggested to originate from leukemic stem cells (LSCs); however, factors regulating self-renewal of LSC and normal hematopoietic stem cells (HSCs) are largely unclear. Here, we show that RalA, a small GTPase in the Ras downstream signaling pathway, has a critical effect on regulating the self-renewal of LSCs and HSCs. A RalA knock-in mouse model (RalARosa26-Tg/+) was initially constructed on the basis of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) assay to analyze normal hematopoietic differentiation frequency using single-cell resolution and flow cytometry. RalA overexpression promoted cell cycle progression and increased the frequency of granulocyte-monocyte progenitors (GMPs), HSCs and multipotent progenitors (MPPs). The uniform manifold approximation and projection (UMAP) plot revealed heterogeneities in HSCs and progenitor cells (HSPCs) and identified the subclusters of HSCs and GMPs with a distinct molecular signature. RalA also promoted BCR-ABL-induced leukemogenesis and self-renewal of primary LSCs and shortened the survival of leukemic mice. RalA knockdown prolonged survival and promoted sensitivity to imatinib in a patient-derived tumor xenograft model. Immunoprecipitation plus single-cell RNA sequencing of the GMP population confirmed that RalA induced this effect by interacting with RAC1. RAC1 inhibition by azathioprine effectively reduced the self-renewal, colony formation ability of LSCs and prolonged the survival in BCR-ABL1-driven RalA overexpression CML mice. Collectively, RalA was detected to be a vital factor that regulates the abilities of HSCs and LSCs, thus facilitating BCR-ABL-triggered leukemia in mice. RalA inhibition serves as the therapeutic approach to eradicate LSCs in CML.
    Keywords:  RalA/single-cell resolution; imatinib resistance; leukemia stem cells; mouse model with gene editing; normal hematopoietic stem cells
    DOI:  https://doi.org/10.7150/ijbs.76993
  6. Blood Adv. 2023 Mar 17. pii: bloodadvances.2022008585. [Epub ahead of print]
    FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.
    Francoise Levavasseur, Samia Oussous, Tuerdi Zubaidan, Olivier Kosmider, Frédéric Pendino, David Rombaut, Didier Bouscary, Michaela Fontenay, Evelyne Lauret, Isabelle Dusanter-Fourt.
      Transcription factor Forkhead box P1 (FOXP1) belongs to the same protein family as the FOXOs that are well-known regulators of murine hematopoietic stem progenitor cell (HSPC) maintenance by dampening oxidative stress. FOXP1 and FOXOs can play opposite or similar roles depending on cell context; they can cross-regulate each other's expression. In a previous study, we have shown that FOXP1 contributes to normal human HSP and acute myeloid leukemia (AML) cell growth. Here we investigated the role of FOXP1 in HSPCs and AML cell oxidative stress defense in human context. FOXP1 expression level was associated with inferior survival outcome of cytogenetically normal (CN) AML patients. FOXP1 knockdown enhanced superoxide anion levels of human committed CD34+CD38+ but not stem cell-enriched CD34+CD38- HSPCs, and AML cells in vitro. It triggered enhanced NRF2 activity and increased cell oxidative stress. FOXP1 had no impact on FOXO1/3/4 expression in these cells; genetic and pharmacological inhibition of FOXOs did not change superoxide anion levels of human HSPCs and AML cells. Also, FOXP1 antioxidant activity was independent of superoxide dismutase (SOD)1-2 or catalase expression changes. Instead, FOXP1 upregulated expression of the stress sensor SIRT1 by stabilizing SIRT1 protein. FOXP1 loss sensitized AML cells to chemotherapy. Altogether, this study identified FOXP1 as a new safeguard against myeloid progenitor oxidative stress, which works independently of FOXOs but through SIRT1, and contributes to AML chemoresistance. It proposes FOXP1 expression/activity as a promising target to overcome drug-resistance of AML HSPCs.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008585
  7. Elife. 2023 Mar 13. pii: e83533. [Epub ahead of print]12
    Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin-beta receptor signaling.
    Xing Feng, Ruifeng Sun, Moonyoung Lee, Xinyue Chen, Shangqin Guo, Huimin Geng, Marcus Müschen, Jungmin Choi, Joao Pedro Pereira.
      Acute lymphoblastic and myeloblastic leukemias (ALL and AML) have been known to modify the bone marrow microenvironment and disrupt non-malignant hematopoiesis. However, the molecular mechanisms driving these alterations remain poorly defined. Using mouse models of ALL and AML, here we show that leukemic cells turn-off lymphopoiesis and erythropoiesis shortly after colonizing the bone marrow. ALL and AML cells express lymphotoxin-a1b2 and activate LTbR signaling in mesenchymal stem cells (MSCs), which turns off IL7 production and prevents non-malignant lymphopoiesis. We show that the DNA damage response pathway and CXCR4 signaling promote lymphotoxin-a1b2 expression in leukemic cells. Genetic or pharmacologic disruption of LTbR signaling in MSCs restores lymphopoiesis but not erythropoiesis, reduces leukemic cell growth, and significantly extends the survival of transplant recipients. Similarly, CXCR4 blocking also prevents leukemia-induced IL7 downregulation, and inhibits leukemia growth. These studies demonstrate that acute leukemias exploit physiological mechanisms governing hematopoietic output as a strategy for gaining competitive advantage.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.83533
  8. Nature. 2023 Mar 15.
    MEN1 mutations mediate clinical resistance to menin inhibition.
    Florian Perner, Eytan M Stein, Daniela V Wenge, Sukrit Singh, Jeonghyeon Kim, Athina Apazidis, Homa Rahnamoun, Disha Anand, Christian Marinaccio, Charlie Hatton, Yanhe Wen, Richard M Stone, David Schaller, Shoron Mowla, Wenbin Xiao, Holly A Gamlen, Aaron J Stonestrom, Sonali Persaud, Elizabeth Ener, Jevon A Cutler, John G Doench, Gerard M McGeehan, Andrea Volkamer, John D Chodera, Radosław P Nowak, Eric S Fischer, Ross L Levine, Scott A Armstrong, Sheng F Cai.
      Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.
    DOI:  https://doi.org/10.1038/s41586-023-05755-9
  9. Res Sq. 2023 Mar 02. pii: rs.3.rs-2544760. [Epub ahead of print]
    Mdm2/p53 levels in bone marrow mesenchymal stromal cells is essential for maintaining the hematopoietic niche in response to DNA damage.
    Rasoul Pourebrahim, Rafael Heinz Montoya, Zoe Alaniz, Lauren Ostermann, Patrick P Lin, Bin Liu, Edward Ayoub, Jared K Burks, Michael Andreeff.
      Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo . We demonstrate that Mdm2 is essential for the emergence, maintenance and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress-associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC-mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is.
    DOI:  https://doi.org/10.21203/rs.3.rs-2544760/v1
  10. bioRxiv. 2023 Mar 01. pii: 2023.02.27.530273. [Epub ahead of print]
    Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.
    Mariam Murtadha, Miso Park, Yinghui Zhu, Enrico Caserta, Ada Alice Dona, Mahmoud Singer, Hawa Vahed, Theophilus Tasndoh, Asaul Gonzalez, Kevin Ly, James F Sanchez, Arnab Chowdhury, Alex Pozhitkov, Lucy Ghoda, Ling Li, Bin Zhang, Amrita Krishnan, Guido Marcucci, John Williams, Flavia Pichiorri.
      Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38 pos ), the presence of CD34 and lack of CD38 expression (CD34 pos CD38 neg ) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34 pos CD38 neg AML blasts, but not in CD34 pos CD38 neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38 pos blasts. Activated CD4 pos and CD8 pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34 pos CD38 neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38 neg and CD38 pos AML blasts, which culminates in LSC depletion.
    Statement of significance: This work represents a potential advancement in the treatment of AML, as it involves the release of IFN-γ by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.
    DOI:  https://doi.org/10.1101/2023.02.27.530273
  11. iScience. 2023 Mar 17. 26(3): 106238
    A multimodal analysis of genomic and RNA splicing features in myeloid malignancies.
    Arda Durmaz, Carmelo Gurnari, Courtney E Hershberger, Simona Pagliuca, Noah Daniels, Hassan Awada, Hussein Awada, Vera Adema, Minako Mori, Ben Ponvilawan, Yasuo Kubota, Tariq Kewan, Waled S Bahaj, John Barnard, Jacob Scott, Richard A Padgett, Torsten Haferlach, Jaroslaw P Maciejewski, Valeria Visconte.
      RNA splicing dysfunctions are more widespread than what is believed by only estimating the effects resulting by splicing factor mutations (SFMT) in myeloid neoplasia (MN). The genetic complexity of MN is amenable to machine learning (ML) strategies. We applied an integrative ML approach to identify co-varying features by combining genomic lesions (mutations, deletions, and copy number), exon-inclusion ratio as measure of RNA splicing (percent spliced in, PSI), and gene expression (GE) of 1,258 MN and 63 normal controls. We identified 15 clusters based on mutations, GE, and PSI. Different PSI levels were present at various extents regardless of SFMT suggesting that changes in RNA splicing were not strictly related to SFMT. Combination of PSI and GE further distinguished the features and identified PSI similarities and differences, common pathways, and expression signatures across clusters. Thus, multimodal features can resolve the complex architecture of MN and help identifying convergent molecular and transcriptomic pathways amenable to therapies.
    Keywords:  Bioinformatics; Cancer; Omics
    DOI:  https://doi.org/10.1016/j.isci.2023.106238
  12. Transplant Cell Ther. 2023 Mar 09. pii: S2666-6367(23)01166-1. [Epub ahead of print]
    TP53 mutations are associated with increased infections and reduced hematopoietic cell transplantation rates in myelodysplastic syndrome and acute myeloid leukemia.
    Jennifer Marvin-Peek, Emily F Mason, Ashwin Kishtagari, Reena V Jayani, Bhagirathbhai Dholaria, Tae Kon Kim, Brian G Engelhardt, Heidi Chen, Stephen Strickland, Bipin Savani, Brent Ferrell, Adetola Kassim, Michael Savona, Sanjay Mohan, Michael Byrne.
       BACKGROUND: Although allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. TP53-mutated (TP53MUT) MDS/AML is particularly high risk, yet fewer TP53MUT patients undergo HCT than other poor-risk TP53-wild type (TP53WT) patients.
    OBJECTIVE: We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting rates of HCT, and therefore investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT.
    STUDY DESIGN: This study was a single center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n=352). HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (OR) for factors associated with HLA typing, HCT, and pre-transplant infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and without TP53 mutations.
    RESULTS: Overall significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%, p=0.028). Development of an infection was significantly associated with decreased odds of HCT (OR=0.42, 95% CI: 0.19-0.90) and worse overall survival (HR=1.46, 95% CI: 1.09-1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR 2.18, 95% CI: 1.21-3.93), bacterial pneumonia (OR 1.83, 95% CI: 1.00-3.33), and invasive fungal infection (OR 2.64, 95% CI: 1.34-5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% vs 19%, p=0.005).
    CONCLUSIONS: With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.
    DOI:  https://doi.org/10.1016/j.jtct.2023.03.008
  13. Leukemia. 2023 Mar 17.
    The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial.
    Kyoo-Hyung Lee, Suk Ran Yoon, Jeong-Ryeol Gong, Eun-Ji Choi, Hun Sik Kim, Chan-Jeoung Park, Sung-Cheol Yun, Soo-Yeon Park, Sol-Ji Jung, Hanna Kim, Soo Yun Lee, Haiyoung Jung, Jae-Eun Byun, Mirang Kim, Seon-Young Kim, Jeong-Hwan Kim, Je-Hwan Lee, Jung-Hee Lee, Yunsuk Choi, Han-Seung Park, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Jimin Woo, Hyeran Kang, Seunghyun Baek, Su Mi Kim, Hoon-Min Kim, Kwang-Hyun Cho, Inpyo Choi.
      Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.
    DOI:  https://doi.org/10.1038/s41375-023-01849-5
  14. Br J Haematol. 2023 Mar 14.
    Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells.
    Xiaoling Xie, Wuju Zhang, Xuan Zhou, Zhixin Ye, Hao Wang, Yingqi Qiu, Yating Pan, Yuxing Hu, Luyao Li, Zhuanzhuan Chen, Wanwen Yang, Yao Lu, Shuxin Zou, Yuhua Li, Xiaochun Bai.
      Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self-renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient-derived xenografts. Importantly, abemaciclib strongly enhanced anti-tumour effects in combination with venetoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor. This treatment combination led to a marked decrease in LSC-enriched populations and resulted in a synergistic anti-leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.
    Keywords:  abemaciclib; acute myeloid leukaemia; differentiation; leukaemia stem cell
    DOI:  https://doi.org/10.1111/bjh.18735
  15. Biochem Pharmacol. 2023 Mar 14. pii: S0006-2952(23)00085-0. [Epub ahead of print] 115494
    Cytarabine-induced destabilization of MCL1 mRNA and protein triggers apoptosis in leukemia cells.
    Jing-Ting Chiou, Chia-Chi Hsu, Ying-Chung Hong, Yuan-Chin Lee, Long-Sen Chang.
      Although cytarabine (Ara-C) is the mainstay of treatment for acute myeloid leukemia (AML), its cytotoxic mechanisms for inducing apoptosis are poorly understood. Therefore, we investigated the Ara-C-induced cell death pathway in human AML U937 cells. Ara-C-induced downregulation of MCL1 is associated with the induction of mitochondrial depolarization and apoptosis. Ara-C triggered NOX4-mediated ROS production, which in turn activated p38 MAPK but inactivated AKT. Ara-C-induced DNA damage modulates p38 MAPK activation without affecting AKT inactivation in U937 cells. Inactivated AKT promotes GSK3β-dependent CREB phosphorylation, which in turn increases NOXA transcription, thereby triggering the degradation of MCL1 protein. Activated p38 MAPK induces HuR downregulation, leading to accelerated MCL1 mRNA turnover. A similar pathway also explains the Ara-C-induced THP-1 cell death. Collectively, our data confirm that Ara-C-triggered apoptosis in the AML cell lines U937 and THP-1 is mediated through the destabilization of MCL1 mRNA and protein. Furthermore, Ara-C acts synergistically with the BCL2 inhibitor ABT-199 to induce cell death in ABT-199-resistant and parental U937 cells by inhibiting MCL1 expression.
    Keywords:  AKT/GSK3β/CREB axis; Cytarabine; HuR axis; Leukemia; MCL1 downregulation; p38 MAPK
    DOI:  https://doi.org/10.1016/j.bcp.2023.115494
  16. Nat Commun. 2023 Mar 17. 14(1): 1497
    Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.
    Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Eva Altrock, Nanni Schmitt, Johanna Flach, Carla Sens-Albert, Felicitas Rapp, Julia Wolf, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Mariia Kuzina, Ahmed Jawhar, Ali Darwich, Cleo-Aron Weis, Alexander Marx, Patrick Wuchter, Victor Costina, Evelyn Jäger, Elena Sperk, Michael Neumaier, Alice Fabarius, Georgia Metzgeroth, Florian Nolte, Laurenz Steiner, Pavel A Levkin, Mohamad Jawhar, Wolf-Karsten Hofmann, Vladimir Riabov, Daniel Nowak.
      Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.
    DOI:  https://doi.org/10.1038/s41467-023-37175-8
  17. Cancer Immunol Immunother. 2023 Mar 17.
    Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia.
    Jiali Cheng, Tong Ge, Xiaojian Zhu, Jue Wang, Yuhao Zeng, Wei Mu, Haodong Cai, Zhenyu Dai, Jin Jin, Yongkun Yang, Guang Hu, Xia Mao, Jianfeng Zhou, Li Zhu, Liang Huang.
       BACKGROUND: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution.
    METHOD: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T.
    RESULTS: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T.
    CONCLUSION: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.
    Keywords:  AML; Antigen density; CD70; Chidamide; Decitabine; Nanobody-CAR T-cells
    DOI:  https://doi.org/10.1007/s00262-023-03422-6
  18. Res Pract Thromb Haemost. 2023 Feb;7(2): 100060
    Platelet function studies in myeloproliferative neoplasms patients with Calreticulin or JAK2 V617F mutation.
    Alexandre Guy, Khalil Helzy, Olivier Mansier, Jean-Claude Bordet, Etienne Rivière, Mathieu Fiore, Chloe James.
       Background: JAK2V617F and Calreticulin (CALR) mutations are the most frequent molecular causes of Phi-negative myeloproliferative neoplasms (MPN). Patients with CALR mutations are at lower risk of thrombosis than patients with JAK2 V617F. We hypothesized that CALR-mutated blood platelets would have platelet function defects that might explain why these patients are at lower risk of thrombosis.
    Objectives: Our main objective was to explore and compare platelet function depending on the MPN molecular marker.
    Methods: We analyzed platelet function in 16 patients with MPN with CALR mutations and 17 patients with JAK2 V617F mutation and compared them with healthy controls. None of these patients was taking antiplatelet therapy. We performed an extensive analysis of platelet function and measured plasmatic soluble P-selectin and CD40L levels.
    Results: We observed significant defects in platelet aggregation, surface glycoprotein expression, fibrinogen binding, and granule content in platelets from patients with MPN compared with that in controls. Moreover, soluble CD40L and P-selectin levels were elevated in patients with MPN compared with that in controls, suggesting an in vivo platelet preactivation. Comparison of platelet function between patients with CALR and JAK2 V617F MPN revealed only minor differences in platelets from patients with CALR. However, these results need to be interpreted within the context of absence of an inflammatory environment that could impact platelet function during MPN.
    Conclusions: These results do not support the hypothesis that calreticulin-mutated platelets have platelet function defects that could explain the lower thrombotic risk of patients with CALR.
    Keywords:  JAK2V617F mutation; blood platelets; calreticulin; myeloproliferative neoplasms; platelet aggregation; thrombosis
    DOI:  https://doi.org/10.1016/j.rpth.2023.100060
  19. Nat Biotechnol. 2023 Mar 13.
    Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia.
    Adrian Gottschlich, Moritz Thomas, Ruth Grünmeier, Stefanie Lesch, Lisa Rohrbacher, Veronika Igl, Daria Briukhovetska, Mohamed-Reda Benmebarek, Binje Vick, Sertac Dede, Katharina Müller, Tao Xu, Dario Dhoqina, Florian Märkl, Sophie Robinson, Andrea Sendelhofert, Heiko Schulz, Öykü Umut, Vladyslav Kavaka, Christina Angeliki Tsiverioti, Emanuele Carlini, Sayantan Nandi, Thaddäus Strzalkowski, Theo Lorenzini, Sophia Stock, Philipp Jie Müller, Janina Dörr, Matthias Seifert, Bruno L Cadilha, Ruben Brabenec, Natalie Röder, Felicitas Rataj, Manuel Nüesch, Franziska Modemann, Jasmin Wellbrock, Walter Fiedler, Christian Kellner, Eduardo Beltrán, Tobias Herold, Dominik Paquet, Irmela Jeremias, Louisa von Baumgarten, Stefan Endres, Marion Subklewe, Carsten Marr, Sebastian Kobold.
      Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development.
    DOI:  https://doi.org/10.1038/s41587-023-01684-0
  20. Leuk Res. 2023 Feb 08. pii: S0145-2126(23)00019-X. [Epub ahead of print]128 107034
    Differential effects of recombinant human thrombopoietin on clinical outcomes in CD7-positive and CD7-negative acute myeloid leukaemia.
    Xiaobai Sun, Yanliang Bai, Mengyi Li, Weiya Li, Haoyan Wang, Mengyu Xiao, Liurui Dou, Juanjuan Song, Junwei Niu, Xingjun Xiao, Yuqing Chen, Kai Sun.
      To investigate the effect of recombinant human thrombopoietin (rhTPO) application on the clinical outcomes of CD7-positive acute myeloid leukaemia (CD7 + AML) patients following chemotherapy, we retrospectively studied 159 newly diagnosed non-M3 AML patients. Patients were divided into the following four groups according to the expression of CD7 in AML blasts and the use of rhTPO after chemotherapy: the CD7 + rhTPO group (n = 41), the CD7 + non-rhTPO group (n = 42), the CD7 negative (CD7-) rhTPO group (n = 37), and the CD7- non-rhTPO group (n = 39). The complete remission rate was higher in the CD7 + rhTPO group than in the CD7 + non-rhTPO group. Importantly, patients in the CD7 + rhTPO group had significantly higher 3-year overall survival (OS) rates and event-free survival (EFS) rates than those in the CD7 + non-rhTPO group, whereas they did not differ statistically between the CD7- rhTPO and CD7- non-rhTPO groups. In addition, multivariate analysis showed that rhTPO was an independent prognostic factor for OS and EFS in CD7 + AML. In conclusion, rhTPO led to better clinical outcomes for patients with CD7 + AML, while it had no significant effect on those with CD7- AML.
    Keywords:  Acute myeloid leukaemia; CD7; Clinical outcome; Recombinant human thrombopoietin
    DOI:  https://doi.org/10.1016/j.leukres.2023.107034
  21. J Clin Oncol. 2023 Mar 17. JCO2201784
    Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes.
    Elisabetta Sauta, Marie Robin, Matteo Bersanelli, Erica Travaglino, Manja Meggendorfer, Lin-Pierre Zhao, Juan Carlos Caballero Berrocal, Claudia Sala, Giulia Maggioni, Massimo Bernardi, Carmen Di Grazia, Luca Vago, Giulia Rivoli, Lorenza Borin, Saverio D'Amico, Cristina Astrid Tentori, Marta Ubezio, Alessia Campagna, Antonio Russo, Daniele Mannina, Luca Lanino, Patrizia Chiusolo, Luisa Giaccone, Maria Teresa Voso, Marta Riva, Esther Natalie Oliva, Matteo Zampini, Elena Riva, Olivier Nibourel, Marilena Bicchieri, Niccolo' Bolli, Alessandro Rambaldi, Francesco Passamonti, Victor Savevski, Armando Santoro, Ulrich Germing, Shahram Kordasti, Valeria Santini, Maria Diez-Campelo, Guillermo Sanz, Francesc Sole, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Matteo Giovanni Della Porta.
       PURPOSE: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.
    METHODS: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed.
    RESULTS: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score.
    CONCLUSION: IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.
    DOI:  https://doi.org/10.1200/JCO.22.01784
  22. PLOS Digit Health. 2023 Mar;2(3): e0000187
    Explainable AI identifies diagnostic cells of genetic AML subtypes.
    Matthias Hehr, Ario Sadafi, Christian Matek, Peter Lienemann, Christian Pohlkamp, Torsten Haferlach, Karsten Spiekermann, Carsten Marr.
      Explainable AI is deemed essential for clinical applications as it allows rationalizing model predictions, helping to build trust between clinicians and automated decision support tools. We developed an inherently explainable AI model for the classification of acute myeloid leukemia subtypes from blood smears and found that high-attention cells identified by the model coincide with those labeled as diagnostically relevant by human experts. Based on over 80,000 single white blood cell images from digitized blood smears of 129 patients diagnosed with one of four WHO-defined genetic AML subtypes and 60 healthy controls, we trained SCEMILA, a single-cell based explainable multiple instance learning algorithm. SCEMILA could perfectly discriminate between AML patients and healthy controls and detected the APL subtype with an F1 score of 0.86±0.05 (mean±s.d., 5-fold cross-validation). Analyzing a novel multi-attention module, we confirmed that our algorithm focused with high concordance on the same AML-specific cells as human experts do. Applied to classify single cells, it is able to highlight subtype specific cells and deconvolve the composition of a patient's blood smear without the need of single-cell annotation of the training data. Our large AML genetic subtype dataset is publicly available, and an interactive online tool facilitates the exploration of data and predictions. SCEMILA enables a comparison of algorithmic and expert decision criteria and can present a detailed analysis of individual patient data, paving the way to deploy AI in the routine diagnostics for identifying hematopoietic neoplasms.
    DOI:  https://doi.org/10.1371/journal.pdig.0000187
  23. Expert Opin Pharmacother. 2023 Mar 15.
    Pharmacotherapeutic advances for splenomegaly in myelofibrosis.
    Douglas Tremblay, John Mascarenhas.
       INTRODUCTION: Myelofibrosis is a hematologic malignancy with a variety of clinical manifestations including splenomegaly, which is present in approximately 80% of newly diagnosed patients. JAK inhibitors are the mainstay of pharmacologic treatment for splenomegaly in myelofibrosis, although spleen size reduction is not universal, and the duration of benefit is only moderately durable.
    AREAS COVERED: We first discuss the pathobiology of splenomegaly in myelofibrosis before detailing approved and novel pharmacotherapies that can reduce spleen size while also highlighting non-pharmacologic approaches. In this review, efficacy of these treatments is measured solely by spleen volume reduction, acknowledging that other outcome measures such as symptom improvement and survival are also critical.
    EXPERT OPINION: Currently, ruxolitinib can be administered to the majority of frontline patients although those with severe thrombocytopenia should receive pacritinib to address spleen burden. Momelotinib may be particularly well suited for patients with significant anemia and novel combination treatments in clinical development may improve the depth and duration of spleen responses. After frontline treatment failure, fedratinib or pacritinib are commercial options for patients with persistent symptomatic splenomegaly. Novel agents given alone or in combination with a JAK inhibitor are being explored in trials which may ameliorate splenomegaly and ultimately improve disease progression.
    Keywords:  JAK inhibition; myelofibrosis; myeloproliferative neoplasms; splenomegaly
    DOI:  https://doi.org/10.1080/14656566.2023.2192350
  24. Cancer Discov. 2023 Mar 17. OF1
    Magrolimab plus Azacitidine Is Safe and Efficacious in High-Risk MDS.
      This combination was safe and met its primary efficacy endpoint of complete remission rate.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-040
  25. Blood. 2023 Mar 16. 141(11): 1237-1238
    MDM2 and BCL-2: to p53 or not to p53?
    Eunice S Wang.
      
    DOI:  https://doi.org/10.1182/blood.2022018739
  26. Br J Haematol. 2023 Mar 14.
    Correction to "Recommendations for laboratory testing of UK patients with acute myeloid leukaemia".
      
    DOI:  https://doi.org/10.1111/bjh.18713
  27. Haematologica. 2023 Mar 16.
    Artificial intelligence to empower diagnosis of myelodysplastic syndromes by multiparametric flow cytometry.
    Valentin Clichet, Delphine Lebon, Nicolas Chapuis, Jaja Zhu, Valérie Bardet, Jean-Pierre Marolleau, Loïc Garçon, Alexis Caulier, Thomas Boyer.
      The diagnosis of myelodysplastic syndromes (MDS) might be challenging and relies on the convergence of cytological, cytogenetic, and molecular arguments. Multiparametric flow cytometry (MFC) helps diagnose MDS, especially when other features are non-contributory, but remains underestimated mostly due to a lack of standardization of cytometers. We present here an innovative model integrating artificial intelligence (AI) with MFC to improve the diagnosis and the classification of MDS. We develop a machine learning model by elasticnet algorithm trained on a cohort of 191 patients and only based on flow cytometry parameters selected by Boruta algorithm, to build a simple but reliable prediction score with 5 parameters. Our MDS prediction score assisted by AI greatly improves the sensitivity of Ogata score while keeping an excellent specificity validated on an external cohort of 89 patients with an AUC = 0.935. This model allows the diagnosis of both high and low risk MDS with 91.8% sensitivity and 92.5% specificity. Interestingly, it highlights a progressive evolution of the score from clonal hematopoiesis of indeterminate potential (CHIP) to highrisk MDS, suggesting a linear evolution between these different stages. By significantly decreasing the overall misclassification of 52% for patients with MDS and of 31.3% for those without MDS (p=0.02), our AI-assisted prediction score outperforms the Ogata score and positions itself as a reliable tool to help diagnose myelodysplastic syndromes.
    DOI:  https://doi.org/10.3324/haematol.2022.282370
  28. Leukemia. 2023 Mar 15.
    Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms.
    Eileen Wedge, Ulvi Ahmadov, Thomas B Hansen, Zongliang Gao, Morten Tulstrup, Christophe Côme, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jakob S Jespersen, Balthasar C Schlotmann, Claudia Schöllkopf, Klas Raaschou-Jensen, Niels Ødum, Jørgen Kjems, Rasmus O Bak, Matthew J Walter, Kirsten Grønbæk, Lasse S Kristensen.
      Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1S34 mutation, in a mouse model with a doxycycline-inducible U2AF1S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1S34 or U2AF1Q157 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1S34 and U2AF1Q157 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
    DOI:  https://doi.org/10.1038/s41375-023-01866-4
  29. Nature. 2023 Mar 15.
    Lactate regulates cell cycle by remodeling the anaphase promoting complex.
    Weihai Liu, Yun Wang, Luiz H M Bozi, Patrick Fischer, Mark P Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna L Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z Xu, Luke Sebastian, Jean Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven P Gygi, Haribabu Arthanari, Edward T Chouchani.
      Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.
    DOI:  https://doi.org/10.1038/s41586-023-05939-3
  30. Blood. 2023 Mar 16. pii: blood.2022016779. [Epub ahead of print]
    Iron homeostasis governs erythroid phenotype in Polycythemia Vera.
    Cavan Bennett, Victoria E Jackson, Anne Pettikiriarachchi, Thomas Hayman, Ute Schaeper, Gemma L Moir-Meyer, Katherine Louise Fielding, Ricardo Ataide, Danielle Clucas, Andrew James Baldi, Alexandra L Garnham, Connie Sn Li-Wai-Suen, Stephen John Loughran, E Joanna Baxter, Anthony R Green, Warren S Alexander, Melanie Bahlo, Kate Burbury, Ashley P Ng, Sant-Rayn Pasricha.
      Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
    DOI:  https://doi.org/10.1182/blood.2022016779
  31. Nature. 2023 Mar 15.
    Whole-genome doubling drives oncogenic loss of chromatin segregation.
    Ruxandra A Lambuta, Luca Nanni, Yuanlong Liu, Juan Diaz-Miyar, Arvind Iyer, Daniele Tavernari, Natalya Katanayeva, Giovanni Ciriello, Elisa Oricchio.
      Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies1-8. However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer.
    DOI:  https://doi.org/10.1038/s41586-023-05794-2
  32. Sci Immunol. 2023 Mar 17. 8(81): eabn6429
    Single-cell dissection of human hematopoietic reconstitution after allogeneic hematopoietic stem cell transplantation.
    Yingying Huo, Linjie Wu, Aiming Pang, Qing Li, Fang Hong, Caiying Zhu, Zining Yang, Weiqian Dai, Yawei Zheng, Qianqian Meng, Jiali Sun, Shihui Ma, Linping Hu, Ping Zhu, Fang Dong, Xin Gao, Erlie Jiang, Sha Hao, Tao Cheng.
      Hematopoietic stem cell transplantation is an effective regenerative therapy for many malignant, inherited, or autoimmune diseases. However, our understanding of reconstituted hematopoiesis in transplant patients remains limited. Here, we uncover the reconstitution dynamics of human allogeneic hematopoietic stem and progenitor cells (HSPCs) at single-cell resolution after transplantation. Transplanted HSPCs underwent rapid and measurable changes during the first 30 days after transplantation, characterized by a strong proliferative response on the first day. Transcriptomic analysis of HSPCs enabled us to observe that immunoregulatory neutrophil progenitors expressing high levels of the S100A gene family were enriched in granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Transplant recipients who developed acute graft-versus-host disease (aGVHD) infused fewer S100Ahigh immunoregulatory neutrophil progenitors, immunophenotyped as Lin-CD34+CD66b+CD177+, than those who did not develop aGVHD. Therefore, our study provides insights into the regenerative process of transplanted HSPCs in human patients and identifies a potential criterion for identifying patients at high risk for developing aGVHD early after transplant.
    DOI:  https://doi.org/10.1126/sciimmunol.abn6429
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