bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021‒05‒23
thirty papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq.
  2. Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia.
  3. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.
  4. Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia.
  5. Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells.
  6. Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course.
  7. SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia.
  8. Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.
  9. 3D tissue engineered plasma cultures support leukemic proliferation and induces drug resistance.
  10. Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21).
  11. Advances in therapeutic options for newly diagnosed, high-risk AML patients.
  12. Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells.
  13. Clinical implications of sequential MRD monitoring by NGS at 2 time points after chemotherapy in patients with AML.
  14. Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter.
  15. Towards precision medicine for AML.
  16. Polycomb Factor PHF19 Controls Cell Growth and Differentiation Toward Erythroid Pathway in Chronic Myeloid Leukemia Cells.
  17. CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag.
  18. Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.
  19. Cancer Stem Cell Metabolism.
  20. Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.
  21. Taming Cell-to-Cell Heterogeneity in Acute Myeloid Leukaemia With Machine Learning.
  22. Functions of RNA N6-methyladenosine modification in acute myeloid leukemia.
  23. Coexistence of BCR-ABL1 and RUNX1-RUNX1T1 in a de novo AML.
  24. Prognosis of comutations in IDH1/2-mutated AML.
  25. Reactive oxygen species in leukemias: maintaining cancer cell proliferation via redox signaling and changing metabolic homeostasis.
  26. Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
  27. Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance.
  28. The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
  29. The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision.
  30. Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients.
  1. Leukemia. 2021 May 21.
    Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq.
    Caner Saygin, Eileen Hu, Pu Zhang, Steven Sher, Arletta Lozanski, Tzyy-Jye Doong, Deedra Nicolet, Shelley Orwick, Jadwiga Labanowska, Jordan N Skinner, Casey Cempre, Tierney Kauffman, Virginia M Goettl, Nyla A Heerema, Lynne Abruzzo, Cecelia Miller, Rosa Lapalombella, Gregory Behbehani, Alice S Mims, Karilyn Larkin, Nicole Grieselhuber, Alison Walker, Bhavana Bhatnagar, Clara D Bloomfield, John C Byrd, Gerard Lozanski, James S Blachly.
      Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
    DOI:  https://doi.org/10.1038/s41375-021-01295-1
  2. Front Oncol. 2021 ;11 659253
    Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia.
    Noortje van Gils, Fedor Denkers, Linda Smit.
      Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapy for many years to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions in the majority of patients, many face a relapse (adaptive resistance) or have refractory disease (primary resistance). Moreover, older patients are often unfit for cytotoxic-based treatment. AML relapse is due to the survival of therapy-resistant leukemia cells (minimal residual disease, MRD). Leukemia cells with stem cell features, named leukemic stem cells (LSCs), residing within MRD are thought to be at the origin of relapse initiation. It is increasingly recognized that leukemia "persisters" are caused by intra-leukemic heterogeneity and non-genetic factors leading to plasticity in therapy response. The BCL2 inhibitor venetoclax, combined with hypomethylating agents or low dose cytarabine, represents an important new therapy especially for older AML patients. However, often there is also a small population of AML cells refractory to venetoclax treatment. As AML MRD reflects the sum of therapy resistance mechanisms, the different faces of treatment "persisters" and LSCs might be exploited to reach an optimal therapy response and prevent the initiation of relapse. Here, we describe the different epigenetic, transcriptional, and metabolic states of therapy sensitive and resistant AML (stem) cell populations and LSCs, how these cell states are influenced by the microenvironment and affect treatment outcome of AML. Moreover, we discuss potential strategies to target dynamic treatment resistance and LSCs.
    Keywords:  acute myeloid leukemia; leukemic stem cells; minimal residual disease; plasticity; therapy resistance
    DOI:  https://doi.org/10.3389/fonc.2021.659253
  3. Nat Commun. 2021 05 18. 12(1): 2901
    RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.
    Ryan M Carr, Denis Vorobyev, Terra Lasho, David L Marks, Ezequiel J Tolosa, Alexis Vedder, Luciana L Almada, Andrey Yurcheko, Ismael Padioleau, Bonnie Alver, Giacomo Coltro, Moritz Binder, Stephanie L Safgren, Isaac Horn, Xiaona You, Eric Solary, Maria E Balasis, Kurt Berger, James Hiebert, Thomas Witzig, Ajinkya Buradkar, Temeida Graf, Peter Valent, Abhishek A Mangaonkar, Keith D Robertson, Matthew T Howard, Scott H Kaufmann, Christopher Pin, Martin E Fernandez-Zapico, Klaus Geissler, Nathalie Droin, Eric Padron, Jing Zhang, Sergey Nikolaev, Mrinal M Patnaik.
      Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
    DOI:  https://doi.org/10.1038/s41467-021-23186-w
  4. Leukemia. 2021 May 17.
    Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia.
    Sarah A Carratt, Theodore P Braun, Cody Coblentz, Zachary Schonrock, Rowan Callahan, Brittany M Smith, Lauren Maloney, Amy C Foley, Julia E Maxson.
      Mutations in SET-binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.
    DOI:  https://doi.org/10.1038/s41375-021-01278-2
  5. Stem Cells. 2021 May 20.
    Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells.
    Paul Jäger, Stefanie Geyh, Sören Twarock, Ron-Patrick Cadeddu, Pablo Rabes, Annemarie Koch, Uwe Maus, Tobias Hesper, Christoph Zilkens, Christina Rautenberg, Felix Bormann, Karl Köhrer, Patrick Petzsch, Dagmar Wieczorek, Beate Betz, Harald Surowy, Barbara Hildebrandt, Ulrich Germing, Guido Kobbe, Rainer Haas, Thomas Schroeder.
      Acute myeloid leukemia (AML) is characterized by an expansion of leukemic cells and a simultaneous reduction of normal hematopoietic precursors in the bone marrow (BM) resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans. Assuming that leukemic cells functionally inhibit healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via humoral factors, we exposed healthy BM-derived CD34+ HSPC to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients. Exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation, and differentiation of healthy CD34+ HSPC. RNA sequencing of healthy CD34+ HSPC after exposure to leukemic conditions revealed a specific signature of genes related to proliferation, cell-cycle regulation, and differentiation, thereby reflecting their functional inhibition on a molecular level. Experiments with paired patient samples showed that these inhibitory effects are markedly related to the immunomagnetically enriched CD34+ leukemic cell population. Using PCR, ELISA, and RNA sequencing, we detected overexpression of TGFβ1 in leukemic cells on the transcriptional and protein level and, correspondingly, a molecular signature related to TGFβ1 signaling in healthy CD34+ HSPC. This inhibitory effect of TGFβ1 on healthy hematopoiesis was functionally corrobated and could be pharmacologically reverted by SD208, an inhibitor of TGFβ receptor 1 signaling. Overall, these data indicate that leukemic cells induce functional inhibition of healthy CD34+ HSPC, at least in part, through TGFβ1, suggesting that blockage of this pathway may improve hematopoiesis in AML.
    Keywords:  CD34+ hematopoietic stem and progenitor cells; acute myeloid leukemia; hematopoietic insufficiency; therapeutic target; transforming growth factor β1
    DOI:  https://doi.org/10.1002/stem.3387
  6. Blood. 2021 May 19. pii: blood.2020009845. [Epub ahead of print]
    Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course.
    Giulia Borella, Ambra Da Ros, Giulia Borile, Elena Porcù, Claudia Tregnago, Maddalena Benetton, Anna Marchetti, Valeria Bisio, Barbara Montini, Barbara Michielotto, Alice Cani, Anna Leszl, Elisabetta Campodoni, Monica Sandri, Monica Montesi, Silvia Bresolin, Stefano Cairo, Barbara Buldini, Franco Locatelli, Martina Pigazzi.
      Bone marrow (BM) microenvironment contributes to the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell-cell interaction and secretion of cytokines that during leukemogenesis are altered and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but still >30% of patients relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the mesenchymal stromal cells (MSCs) role in the leukemic niche to define its contribution to the mechanisms of leukemia escape. We generated humanized three-dimensional (3D) niche with AML cells and MSCs derived from either patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation, and severely compromising their immunomodulatory capability. We confirmed that AML cells modulate h-MSCs transcriptional profile promoting functions similar to the AML-MSCs when co-cultured in vitro, thus facilitating leukemia progression. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features, at transcriptional and functional levels, including the secretome. We proved that AML blasts alter MSCs activities in the BM niche, favoring disease development and progression. We discovered that a novel AML-MSCs selective CaV1.2 channel blocker drug, Lercanidipine, is able to impair leukemia progression in 3D niche both in vitro and when implanted in vivo, if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.
    DOI:  https://doi.org/10.1182/blood.2020009845
  7. Leukemia. 2021 May 17.
    SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia.
    Inge van der Werf, Anna Wojtuszkiewicz, Huilan Yao, Rocco Sciarrillo, Manja Meggendorfer, Stephan Hutter, Wencke Walter, Jeroen Janssen, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, Gerrit Jansen, Gertjan J L Kaspers, Richard Groen, Gert Ossenkoppele, Jacqueline Cloos.
      
    DOI:  https://doi.org/10.1038/s41375-021-01273-7
  8. Blood Cancer J. 2021 May 20. 11(5): 98
    Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.
    Warren Fiskus, Christopher P Mill, Behnam Nabet, Dimuthu Perera, Christine Birdwell, Taghi Manshouri, Bernardo Lara, Tapan M Kadia, Courtney DiNardo, Koichi Takahashi, Naval Daver, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Steven Kornblau, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia Manero, Sunil Sharma, Matthew Stubbs, Xiaoping Su, Michael R Green, Cristian Coarfa, Srdan Verstovsek, Joseph D Khoury, Christopher R Vakoc, Kapil N Bhalla.
      There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.
    DOI:  https://doi.org/10.1038/s41408-021-00487-3
  9. Leuk Lymphoma. 2021 May 17. 1-9
    3D tissue engineered plasma cultures support leukemic proliferation and induces drug resistance.
    Kinan Alhallak, Pilar de la Puente, Amanda Jeske, Jennifer Sun, Barbara Muz, Michael P Rettig, Ilyas Sahin, Ellen L Weisberg, James D Griffin, John L Reagan, John F DiPersio, Abdel Kareem Azab.
      Chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) are hematological malignancies that remain incurable despite novel treatments. In order to improve current treatments and clinical efficacy, there remains a need for more complex in vitro models that mimic the intricate human leukemic microenvironment. This study aimed to use 3D tissue engineered plasma cultures (3DTEPC) derived from CML, AML and CLL patients to promote proliferation of leukemic cells for use as a drug screening tool for treatment. 3DTEPC supported the growth of primary CML, AML and CLL cells and also induced significantly more drug resistance in CML, AML and CLL cell lines compared to 2D. The 3DTEPC created a more physiologically relevant environment for leukemia cell proliferation, provided a reliable model for growing leukemia patient samples, and serves as a relevant tool for drug screening and personalized medicine.
    Keywords:  Leukemia; drug resistance; patient-derived 3D culture
    DOI:  https://doi.org/10.1080/10428194.2021.1919657
  10. Blood Adv. 2021 May 25. 5(10): 2481-2489
    Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21).
    Se Young Han, Krzysztof Mrózek, Jenna Voutsinas, Qian Wu, Elizabeth A Morgan, Hanne Vestergaard, Robert Ohgami, Philip M Kluin, Thomas Kielsgaard Kristensen, Sheeja Pullarkat, Michael Boe Møller, Ana-Iris Schiefer, Linda B Baughn, Young Kim, David Czuchlewski, Jacobien R Hilberink, Hans-Peter Horny, Tracy I George, Michelle Dolan, Nam K Ku, Cecilia Arana Yi, Vinod Pullarkat, Jessica Kohlschmidt, Amandeep Salhotra, Lori Soma, Clara D Bloomfield, Dong Chen, Wolfgang R Sperr, Guido Marcucci, Christina Cho, Cem Akin, Jason Gotlib, Sigurd Broesby-Olsen, Melissa Larson, Michael A Linden, H Joachim Deeg, Gregor Hoermann, Miguel-Angel Perales, Jason L Hornick, Mark R Litzow, Ryotaro Nakamura, Daniel Weisdorf, Gautam Borthakur, Gerwin Huls, Peter Valent, Celalettin Ustun, Cecilia C S Yeung.
      Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).
    DOI:  https://doi.org/10.1182/bloodadvances.2020003605
  11. Ther Adv Hematol. 2021 ;12 20406207211001138
    Advances in therapeutic options for newly diagnosed, high-risk AML patients.
    Kimberley Doucette, Judith Karp, Catherine Lai.
      Acute myeloid leukemia (AML) is an aggressive malignancy characterized by clonal proliferation of neoplastic immature precursor cells. AML impacts older adults and has a poor prognosis. Despite recent advances in treatment, AML is complex, with both genetic and epigenetic aberrations in the malignant clone and elaborate interactions with its microenvironment. We are now able to stratify patients on the basis of specific clinical and molecular features in order to optimize individual treatment strategies. However, our understanding of the complex nature of these molecular abnormalities continues to expand the defining characteristics of high-risk mutations. In this review, we focus on genetic and microenvironmental factors in adverse risk AML that play critical roles in leukemogenesis, including those not described in an European LeukemiaNet adverse risk group, and describe therapies that are currently in the clinical arena, either approved or under development.
    Keywords:  acute myeloid leukemia; adverse risk; high risk; newly diagnosed; therapy
    DOI:  https://doi.org/10.1177/20406207211001138
  12. Leukemia. 2021 May 17.
    Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells.
    Manja Wobus, Anna Mies, Nandini Asokan, Uta Oelschlägel, Kristin Möbus, Susann Winter, Michael Cross, Heike Weidner, Martina Rauner, Lorenz C Hofbauer, Martin Bornhäuser, Uwe Platzbecker.
      The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
    DOI:  https://doi.org/10.1038/s41375-021-01275-5
  13. Blood Adv. 2021 May 25. 5(10): 2456-2466
    Clinical implications of sequential MRD monitoring by NGS at 2 time points after chemotherapy in patients with AML.
    Cheng-Hong Tsai, Jih-Luh Tang, Feng-Ming Tien, Yuan-Yeh Kuo, Dung-Chi Wu, Chien-Chin Lin, Mei-Hsuan Tseng, Yen-Ling Peng, Mei-Fang Hou, Yi-Kuang Chuang, Ming-Chih Liu, Chia-Wen Liu, Ming Yao, Liang-In Lin, Wen-Chien Chou, Chien-Yu Chen, Hsin-An Hou, Hwei-Fang Tien.
      Next-generation sequencing (NGS) has been applied to measurable/minimal residual disease (MRD) monitoring after induction chemotherapy in patients with acute myeloid leukemia (AML), but the optimal time point for the test remains unclear. In this study, we aimed to investigate the clinical significance of NGS MRD at 2 different time points. We performed targeted NGS of 54 genes in bone marrow cells serially obtained at diagnosis, first complete remission (first time point), and after the first consolidation chemotherapy (second time point) from 335 de novo AML patients. Excluding DNMT3A, TET2, and ASXL1 mutations, which are commonly present in individuals with clonal hematopoiesis of indeterminate potential, MRD could be detected in 46.4% of patients at the first time point (MRD1st), and 28.9% at the second time point (MRD2nd). The patients with detectable NGS MRD at either time point had a significantly higher cumulative incidence of relapse and shorter relapse-free survival and overall survival. In multivariate analysis, MRD1st and MRD2nd were both independent poor prognostic factors. However, the patients with positive MRD1st but negative MRD2nd had a similar good prognosis as those with negative MRD at both time points. The incorporation of multiparameter flow cytometry and NGS MRD revealed that the presence of NGS MRD predicted poorer prognosis among the patients without detectable MRD by multiparameter flow cytometry at the second time point but not the first time point. In conclusion, the presence of NGS MRD, especially after the first consolidation therapy, can help predict the clinical outcome of AML patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003738
  14. Blood. 2021 May 19. pii: blood.2020008971. [Epub ahead of print]
    Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter.
    Emiel van der Kouwe, Gerwin Heller, Akos Czibere, John A Pulikkan, Christiane Agreiter, Lucio H Castilla, Ruud Delwel, Annalisa Di Ruscio, Alexander K Ebralidze, Maurizio Forte, Florian Grebien, Elizabeth Heyes, Lukas Kazianka, Julian Klinger, Christoph Kornauth, Trang Le, Karin Lind, Inês Amorim Monteiro Barbosa, Tea Pemovska, Alexander Sebastian Pichler, Ann-Sofie Schmolke, Carmen Marita Schweicker, Heinz Sill, Wolfgang R Sperr, Andreas Spittler, Sridevi Surapally, Bon Q Trinh, Peter Valent, Katrina Vanura, Robert S Welner, Johannes Zuber, Daniel G Tenen, Philipp B Staber.
      The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we demonstrate that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving non-coding antisense transcription. Core binding factor (CBF) fusions, RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense towards antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.
    DOI:  https://doi.org/10.1182/blood.2020008971
  15. Nat Rev Clin Oncol. 2021 May 18.
    Towards precision medicine for AML.
    Hartmut Döhner, Andrew H Wei, Bob Löwenberg.
      With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges.
    DOI:  https://doi.org/10.1038/s41571-021-00509-w
  16. Front Cell Dev Biol. 2021 ;9 655201
    Polycomb Factor PHF19 Controls Cell Growth and Differentiation Toward Erythroid Pathway in Chronic Myeloid Leukemia Cells.
    Marc García-Montolio, Cecilia Ballaré, Enrique Blanco, Arantxa Gutiérrez, Sergi Aranda, Antonio Gómez, Chung H Kok, David T Yeung, Timothy P Hughes, Pedro Vizán, Luciano Di Croce.
      Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation, and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb repressor complex 2 (PRC2), often upregulated in human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cells. We demonstrated that PHF19 depletion decreases cell proliferation and promotes chronic myeloid leukemia (CML) differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through a direct regulation of the cell cycle inhibitor p21. Furthermore, we observed that MTF2, a PHF19 homolog, partially compensates for PHF19 depletion in a subset of target genes, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential therapeutic target for myeloid leukemia treatment.
    Keywords:  PHF19; chronic myeloid leukemia; epigenetics; erythroid differentiation; polycomb
    DOI:  https://doi.org/10.3389/fcell.2021.655201
  17. Blood. 2021 May 19. pii: blood.2020010567. [Epub ahead of print]
    CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag.
    Francesca Basso-Valentina, Gabriel Levy, Leila N Varghese, Myriam Oufadem, Benedicte Neven, Charlotte Boussard, Nathalie Balayn, Caroline Marty, William Vainchenker, Isabelle Plo, Paola Ballerini, Stefan N Constantinescu, Remi Favier, Hana Raslova.
      Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in one consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. NGS revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated to its retention in the endoplasmic reticulum. The low cell surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm-associated calreticulin mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant calreticulin mutant protein. Finally, the endogenous calreticulin mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.
    DOI:  https://doi.org/10.1182/blood.2020010567
  18. Am Soc Clin Oncol Educ Book. 2021 Mar;41 328-350
    Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.
    Robert P Hasserjian, Rena Buckstein, Mrinal M Patnaik.
      Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.
    DOI:  https://doi.org/10.1200/EDBK_320113
  19. Adv Exp Med Biol. 2021 ;1311 161-172
    Cancer Stem Cell Metabolism.
    Fidelia B Alvina, Arvin M Gouw, Anne Le.
      Cancer stem cells (CSCs), also known as tumorinitiating cells (TICs), are a group of cells found within cancer cells. Like normal stem cells, CSCs can proliferate, engage in self-renewal, and are often implicated in the recurrence of tumors after therapy [1, 2]. The existence of CSCs in various types of cancer has been proven, such as in acute myeloid leukemia (AML) [3], breast [4], pancreatic [5], and lung cancers [6], to name a few. There are two theories regarding the origin of CSCs. First, CSCs may have arisen from normal stem/progenitor cells that experienced changes in their environment or genetic mutations. On the other hand, CSCs may also have originated from differentiated cells that underwent genetic and/or heterotypic modifications [7]. Either way, CSCs reprogram their metabolism in order to support tumorigenesis.
    Keywords:  Cancer stem cell; Glucose metabolism; Glutamine metabolism; Lipid metabolism; Metabolic plasticity; Mitochondrial metabolism
    DOI:  https://doi.org/10.1007/978-3-030-65768-0_12
  20. Front Oncol. 2021 ;11 663406
    Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.
    Ramin Radpour, Miriam Stucki, Carsten Riether, Adrian F Ochsenbein.
      Background: Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.Methods: To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.
    Results: We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.
    Conclusions: Our results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.
    Keywords:  CD4+ T cell; CD8+ T cell; acute myeloid leukemia; epigenetics (chromatin remodelling); histone (de)acetylation; immune-checkpoints; immunotherapy; leukemia stem cell (LSC)
    DOI:  https://doi.org/10.3389/fonc.2021.663406
  21. Front Oncol. 2021 ;11 666829
    Taming Cell-to-Cell Heterogeneity in Acute Myeloid Leukaemia With Machine Learning.
    Yara E Sánchez-Corrales, Ruben V C Pohle, Sergi Castellano, Alice Giustacchini.
      Acute Myeloid Leukaemia (AML) is a phenotypically and genetically heterogenous blood cancer characterised by very poor prognosis, with disease relapse being the primary cause of treatment failure. AML heterogeneity arise from different genetic and non-genetic sources, including its proposed hierarchical structure, with leukemic stem cells (LSCs) and progenitors giving origin to a variety of more mature leukemic subsets. Recent advances in single-cell molecular and phenotypic profiling have highlighted the intra and inter-patient heterogeneous nature of AML, which has so far limited the success of cell-based immunotherapy approaches against single targets. Machine Learning (ML) can be uniquely used to find non-trivial patterns from high-dimensional datasets and identify rare sub-populations. Here we review some recent ML tools that applied to single-cell data could help disentangle cell heterogeneity in AML by identifying distinct core molecular signatures of leukemic cell subsets. We discuss the advantages and limitations of unsupervised and supervised ML approaches to cluster and classify cell populations in AML, for the identification of biomarkers and the design of personalised therapies.
    Keywords:  AML; classification; clustering; leukaemia; machine learning
    DOI:  https://doi.org/10.3389/fonc.2021.666829
  22. Biomark Res. 2021 May 17. 9(1): 36
    Functions of RNA N6-methyladenosine modification in acute myeloid leukemia.
    Xue Zheng, Yuping Gong.
      Acute myeloid leukemia (AML) is a hematologic malignancy with an unfavorable prognosis. A better understanding of AML pathogenesis and chemotherapy resistance at the molecular level is essential for the development of new therapeutic strategies. Apart from DNA methylation and histone modification, RNA epigenetic modification, another layer of epigenetic modification, also plays a critical role in gene expression regulation. Among the more than 150 kinds of RNA epigenetic modifications, N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes and is involved in various biological processes, such as circadian rhythms, adipogenesis, T cell homeostasis, spermatogenesis, and the heat shock response. As a reversible and dynamic modification, m6A is deposited on specific target RNA molecules by methyltransferases and is removed by demethylases. Moreover, m6A binding proteins recognize m6A modifications, influencing RNA splicing, stability, translation, nuclear export, and localization at the posttranscriptional level. Emerging evidence suggests that dysregulation of m6A modification is involved in tumorigenesis, including that of AML. In this review, we summarize the most recent advances regarding the biological functions and molecular mechanisms of m6A RNA methylation in normal hematopoiesis, leukemia cell proliferation, apoptosis, differentiation, therapeutic resistance, and leukemia stem cell/leukemia initiating cell (LSC/LIC) self-renewal. In addition, we discuss how m6A regulators are closely correlated with the clinical features of AML patients and may serve as new biomarkers and therapeutic targets for AML.
    Keywords:  Acute myeloid leukemia; Epigenetics; N6-methyladenosine (m6A); RNA methylation
    DOI:  https://doi.org/10.1186/s40364-021-00293-w
  23. Blood. 2021 May 20. 137(20): 2853
    Coexistence of BCR-ABL1 and RUNX1-RUNX1T1 in a de novo AML.
    Rumina Musani, Hong Chang.
      
    DOI:  https://doi.org/10.1182/blood.2021011517
  24. Blood. 2021 May 20. 137(20): 2856
    Prognosis of comutations in IDH1/2-mutated AML.
      
    DOI:  https://doi.org/10.1182/blood.2021012066
  25. Oncotarget. 2021 May 11. 12(10): 952-954
    Reactive oxygen species in leukemias: maintaining cancer cell proliferation via redox signaling and changing metabolic homeostasis.
    Andrew J Robinson, Richard L Darley, Alex Tonks.
      
    Keywords:  AML; REDOX; ROS; glycolysis; metabolism
    DOI:  https://doi.org/10.18632/oncotarget.27913
  26. Mol Cell. 2021 May 20. pii: S1097-2765(21)00320-8. [Epub ahead of print]81(10): 2183-2200.e13
    Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
    Simon J Hogg, Olga Motorna, Leonie A Cluse, Timothy M Johanson, Hannah D Coughlan, Ramya Raviram, Robert M Myers, Matteo Costacurta, Izabela Todorovski, Lizzy Pijpers, Stefan Bjelosevic, Tobias Williams, Shannon N Huskins, Conor J Kearney, Jennifer R Devlin, Zheng Fan, Jafar S Jabbari, Ben P Martin, Mohamed Fareh, Madison J Kelly, Daphné Dupéré-Richer, Jarrod J Sandow, Breon Feran, Deborah Knight, Tiffany Khong, Andrew Spencer, Simon J Harrison, Gareth Gregory, Vihandha O Wickramasinghe, Andrew I Webb, Phillippa C Taberlay, Kenneth D Bromberg, Albert Lai, Anthony T Papenfuss, Gordon K Smyth, Rhys S Allan, Jonathan D Licht, Dan A Landau, Omar Abdel-Wahab, Jake Shortt, Stephin J Vervoort, Ricky W Johnstone.
      To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
    Keywords:  H3K27ac; P300/CBP; cancer; chromatin biology; epigenetics; histone acetylation; histone deacetylase; histone methylation; lysine acetylation; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2021.04.015
  27. Leukemia. 2021 May 18.
    Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance.
    Ting Song, Yafei Guo, Zuguang Xue, Zongwei Guo, Ziqian Wang, Donghai Lin, Hong Zhang, Hao Pan, Xiaodong Zhang, Fangkui Yin, Hang Wang, Laura Bonnette Uwituze, Zhichao Zhang.
      Herein, we screened a novel inhibitor of the Hsp70-Bim protein-protein interaction (PPI), S1g-2, from a Bcl-2 inhibitor library; this compound specifically disrupted the Hsp70-Bim PPI by direct binding to an unknown site adjacent to that of an allosteric Hsp70 inhibitor MKT-077, showing binding affinity in sub-μM concentration range. S1g-2 exhibited overall 5-10-fold higher apoptosis-inducing activity in CML cells, primary CML blasts, and BCR-ABL-transformed BaF3 cells than other cancer cells, normal lymphocytes, and BaF3 cells, illustrating Hsp70-Bim PPI driven by BCR-ABL protects CML through oncoclient proteins that enriched in three pathways: eIF2 signaling, the regulation of eIF4E and p70S6K signaling, and the mTOR signaling pathways. Moreover, S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines and is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients. By comparing the underlying mechanisms of S1g-2, MKT-077, and an ATP-competitive Hsp70 inhibitor VER-155008, the Hsp70-Bim PPI was identified to be a CML-specific target to protect from TKIs through the above three oncogenic signaling pathways. The in vivo activity against CML and low toxicity endows S1g-2 a first-in-class promising drug candidate for both TKI-sensitive and resistant CML.
    DOI:  https://doi.org/10.1038/s41375-021-01283-5
  28. Cell. 2021 May 12. pii: S0092-8674(21)00502-X. [Epub ahead of print]
    The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
    Stephin J Vervoort, Sarah A Welsh, Jennifer R Devlin, Elisa Barbieri, Deborah A Knight, Sarah Offley, Stefan Bjelosevic, Matteo Costacurta, Izabela Todorovski, Conor J Kearney, Jarrod J Sandow, Zheng Fan, Benjamin Blyth, Victoria McLeod, Joseph H A Vissers, Karolina Pavic, Ben P Martin, Gareth Gregory, Elena Demosthenous, Magnus Zethoven, Isabella Y Kong, Edwin D Hawkins, Simon J Hogg, Madison J Kelly, Andrea Newbold, Kaylene J Simpson, Otto Kauko, Kieran F Harvey, Michael Ohlmeyer, Jukka Westermarck, Nathanael Gray, Alessandro Gardini, Ricky W Johnstone.
      Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.
    Keywords:  CDK9; CRISPR-Cas9 screen; CTD; Integrator; PP2A; PP2A activation; RNA polymerase II; cancer; pause-release; phosphatase; transcriptional elongation
    DOI:  https://doi.org/10.1016/j.cell.2021.04.022
  29. Leukemia. 2021 May 21.
    The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision.
    Friederike Herbst, Tonio J L Lang, Elias S P Eckert, Peer Wünsche, Alexander A Wurm, Tim Kindinger, Karin Laaber, Shayda Hemmati, Agnes Hotz-Wagenblatt, Oksana Zavidij, Anna Paruzynski, Junyan Lu, Christof von Kalle, Thorsten Zenz, Christoph Klein, Manfred Schmidt, Claudia R Ball, Hanno Glimm.
      Protein-coding and non-coding genes like miRNAs tightly control hematopoietic differentiation programs. Although miRNAs are frequently located within introns of protein-coding genes, the molecular interplay between intronic miRNAs and their host genes is unclear. By genomic integration site mapping of gamma-retroviral vectors in genetically corrected peripheral blood from gene therapy patients, we identified the EVL/MIR342 gene locus as a hotspot for therapeutic vector insertions indicating its accessibility and expression in human hematopoietic stem and progenitor cells. We therefore asked if and how EVL and its intronic miRNA-342 regulate hematopoiesis. Here we demonstrate that overexpression (OE) of Evl in murine primary Lin- Sca1+ cKit+ cells drives lymphopoiesis whereas miR-342 OE increases myeloid colony formation in vitro and in vivo, going along with a profound upregulation of canonical pathways essential for B-cell development or myelopoietic functions upon Evl or miR-342 OE, respectively. Strikingly, miR-342 counteracts its host gene by targeting lymphoid signaling pathways, resulting in reduced pre-B-cell output. Moreover, EVL overexpression is associated with lymphoid leukemia in patients. In summary, our data show that one common gene locus regulates distinct hematopoietic differentiation programs depending on the gene product expressed, and that the balance between both may determine hematopoietic cell fate decision.
    DOI:  https://doi.org/10.1038/s41375-021-01267-5
  30. Leukemia. 2021 May 19.
    Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients.
    Tiziano Barbui, Valerio De Stefano, Alessandra Carobbio, Alessandra Iurlo, Alberto Alvarez-Larran, Beatriz Cuevas, Francisca Ferrer Marín, Alessandro M Vannucchi, Francesca Palandri, Claire Harrison, Hassan Sibai, Martin Griesshammer, Massimiliano Bonifacio, Elena M Elli, Chiara Trotti, Steffen Koschmieder, Giuseppe Carli, Giulia Benevolo, Jean-Christophe Ianotto, Swati Goel, Anna Falanga, Silvia Betti, Daniele Cattaneo, Eduardo Arellano-Rodrigo, Lara Mannelli, Nicola Vianelli, Andrew Doyle, Vikas Gupta, Kai Wille, Douglas Tremblay, John Mascarenhas.
      
    DOI:  https://doi.org/10.1038/s41375-021-01279-1
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:24:35.