bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021‒11‒21
twenty-six papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study.
  2. PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in Acute Myeloid Leukemia.
  3. Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia.
  4. Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study.
  5. Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C.
  6. Implementing a functional precision medicine tumor board for acute myeloid leukemia.
  7. Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells.
  8. Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells.
  9. A review of FLT3 inhibitors in acute myeloid leukemia.
  10. MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common β Chain Cytokine Receptor Endocytosis.
  11. The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia.
  12. Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries.
  13. DNMT3A Overgrowth Syndrome is associated with the development of hematopoietic malignancies in children and young adults.
  14. A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia.
  15. A B-cell developmental gene regulatory network is activated in infant AML.
  16. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.
  17. Activated naïve γδ T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia.
  18. NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.
  19. Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators.
  20. Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation.
  21. Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9.
  22. Gemtuzumab ozogamicin in (KMT2A)-rearranged adult acute myeloid leukaemia (AML) in the UK Medical Research Council AML15 and AML16 trials.
  23. Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.
  24. Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype.
  25. Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen.
  26. CD62L expression level determines the cell fate of myeloid progenitors.
  1. Blood Adv. 2021 Nov 18. pii: bloodadvances.2021004934. [Epub ahead of print]
    Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study.
    Jan Moritz Middeke, Klaus H Metzeler, Christoph Röllig, Michael Kramer, Jan-Niklas Eckardt, Sebastian Stasik, Philipp A Greif, Karsten Spiekermann, Maja Rothenberg-Thurley, Utz Krug, Jan Braess, Alwin Kraemer, Andreas Hochhaus, Tim Henrik Brümmendorf, Ralph Naumann, Björn Steffen, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Dennis Görlich, Cristina M Sauerland, Kerstin Schaefer-Eckart, Christoph Schliemann, Stefan W Krause, Mathias Hänel, Norbert Frickhofen, Richard Noppeney, Ulrich Kaiser, Martin Kaufmann, Desiree Kunadt, Bernhard Woermann, Katja Sockel, Malte von Bonin, Tobias Herold, Carsten Müller-Tidow, Uwe Platzbecker, Wolfgang E Berdel, Hubert Serve, Claudia D Baldus, Gerhard Ehninger, Johannes Schetelig, Wolfgang Hiddemann, Martin Bornhäuser, Friedrich Stölzel, Christian Thiede.
      Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004934
  2. Blood. 2021 Nov 17. pii: blood.2020010344. [Epub ahead of print]
    PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in Acute Myeloid Leukemia.
    Swagata Goswami, Rajeswaran Mani, Jessica Nunes, Chi-Ling Chiang, Kevan Zapolnik, Eileen Y Hu, Frank W Frissora, Xiaokui M Mo, Logan A Walker, Pearlly S Yan, Ralf Bundschuh, Larry Beaver, Raymond David Devine, Yo-Ting Tsai, Ann Marie Ventura, Zhiliang Xie, Min Chen, Rosa Lapalombella, Alison R Walker, Alice S Mims, Karilyn Larkin, Nicole Renee Grieselhuber, Chad Bennett, Mitch A Phelps, Erin Hertlein, Gregory K Behbehani, Sumithira Vasu, John C Byrd, Natarajan Muthusamy.
      Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. Herein, we identified that the silencing of Protein Phosphatase 2A (PP2A) directly contributes to differentiation block in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling reveal that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent OSU-2S in parallel with genetic approaches, we discovered that PP2A enforces c-Myc and p21 dependent terminal differentiation, proliferation arrest and apoptosis in AML. Finally, we demonstrate that PP2A activation decreases leukemia initiating stem cells, increases leukemic blast maturation, and improves overall survival in murine Tet2-/-Flt3ITD/WT and human AML models in-vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.
    DOI:  https://doi.org/10.1182/blood.2020010344
  3. Mol Cancer Res. 2021 Nov 19. pii: molcanres.MCR-21-0390-A.2021. [Epub ahead of print]
    Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia.
    Florencia Rago, Lindsey Ulkus Rodrigues, Megan Bonney, Kathleen Sprouffske, Esther Kurth, GiNell Elliott, Jessi Ambrose, Peter Aspesi, Justin Oborski, Julie T Chen, E Robert McDonald, Felipa A Mapa, David A Ruddy, Audrey Kauffmann, Tinya Abrams, Hyo-Eun C Bhang, Zainab Jagani.
      Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myeloid leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared to other lineages. This result was striking in comparison to data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes including MYC, a well-established target of BRG1 activity in AML. Overall, small molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Implications: Our studies reveal the breadth of SWI/SNF dependency in leukemia and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0390
  4. Blood Adv. 2021 Nov 18. pii: bloodadvances.2021005335. [Epub ahead of print]
    Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study.
    David Martínez-Cuadrón, Juan Eduardo Megías-Vericat, Josefina Serrano, Pilar Martínez-Sánchez, Eduardo Rodríguez-Arbolí, Cristina Gil, Eliana Aguiar, Juan Miguel Bergua Burgues, Jose L Lopez-Lorenzo, Teresa Bernal, Ana Espadana, Mercedes Colorado, Carlos Rodríguez-Medina, María López-Pavia, Mar Tormo, Jesus Lorenzo Algarra, Maria Luz Amigo, Maria Jose Sayas, Jorge Labrador, Juan I Rodríguez-Gutiérrez, Celina Benavente, Lissette Costilla-Barriga, Raimundo García-Boyero, Esperanza Lavilla, Susana Vives, Pilar Herrera, Daniel García, María Mar Herráez-Albendea, Graça V Esteves, María Isabel Gómez-Roncero, Ana Cabello, Guiomar Bautista, Amaia Balerdi, José Mariz, Blanca Boluda, Miguel A Sanz, Pau Montesinos.
      Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients, and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns and outcomes of sAML adult patients of the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) sAML, divided into myelodysplastic syndrome (MDS-AML, 44%), MDS/myeloproliferative (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared to de novo, sAML were older (median age 69 years old), had more ECOG ≥2 (35%) or high-risk cytogenetics (40%), less FLT3-ITD (11%) and NPM1 mutations (21%), and received less intensive chemotherapy regimens (38%) (all P<0.001). Median OS was higher in de novo than in sAML (10.9 vs 5.6 months, P<0.001); and shorter in sAML after hematologic disorder (MDS, MDS/MPN or MPN) as compared to t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively, P=0.04). After intensive chemotherapy, median OS was better among de novo and neo-AML patients (17.2 and 14.6 months). No OS differences were observed after hypomethylating agents according to type of AML. sAML was as an independent adverse prognostic factor for OS. We confirm high prevalence and adverse features of sAML and we establish its independent adverse prognostic value. This study was registered at www.clinicaltrials.gov as #NCT02607059.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005335
  5. Oncogenesis. 2021 Nov 17. 10(11): 79
    Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C.
    Kuangguo Zhou, Mi Zhou, Ling Cheng, Xing Chen, Xiaomin Wang, Yajing Chu, Qilin Yu, Shu Zhang, Na Wang, Lei Zhao, Di Wang, Liang Huang, Congyi Wang, Weiping Yuan, Jianfeng Zhou.
      Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.
    DOI:  https://doi.org/10.1038/s41389-021-00366-3
  6. Cancer Discov. 2021 Nov 17. pii: candisc.0410.2021. [Epub ahead of print]
    Implementing a functional precision medicine tumor board for acute myeloid leukemia.
    Disha Malani, Ashwini Kumar, Oscar Bruck, Mika Kontro, Bhagwan Yadav, Monica Hellesoy, Heikki Kuusanmaki, Olli Dufva, Matti Kankainen, Samuli Eldfors, Swapnil Potdar, Jani Saarela, Laura Turunen, Alun Parsons, Imre Vastrik, Katja Kivinen, Janna Saarela, Riikka Raty, Minna Lehto, Maija Wolf, Bjorn Tore Gjertsen, Satu Mustjoki, Tero Aittokallio, Krister Wennerberg, Caroline A Heckman, Olli Kallioniemi, Kimmo Porkka.
      We generated ex vivo drug response and multi-omics profiling data for a prospective series of 252 samples from 186 acute myeloid leukemia (AML) patients. Functional precision medicine tumor board (FPMTB) integrated clinical, molecular and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of AML patients and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five AML patients to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3-inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0410
  7. Br J Haematol. 2021 Nov 18.
    Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells.
    Helal Mohammed Mohammed Ahmed, Subbaiah Chary Nimmagadda, Yahya S Al-Matary, Maren Fiori, Tobias May, Daria Frank, Pradeep Kumar Patnana, Christian Récher, Christoph Schliemann, Jan-Henrik Mikesch, Thorsten Koenig, Frank Rosenbauer, Wolfgang Hartmann, Jan Tuckermann, Ulrich Dührsen, Wei Lanying, Martin Dugas, Bertram Opalka, Georg Lenz, Cyrus Khandanpour.
      Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing chemotherapy-induced apoptosis. This encouraged us to investigate leukaemia-BM niche-associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells' proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients.
    Keywords:  acute myeloid leukaemia; bone marrow microenvironment; dexamethasone; mesenchymal stromal cell; notch
    DOI:  https://doi.org/10.1111/bjh.17940
  8. Front Oncol. 2021 ;11 769730
    Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells.
    Yilin Chen, Jing Zou, Fanjun Cheng, Weiming Li.
      The therapeutic landscape for chronic myeloid leukemia (CML) has improved significantly with the approval of tyrosine kinase inhibitors (TKIs) for therapeutic use. Most patients with optimal responses to TKIs can have a normal life expectancy. Treatment-free remission (TFR) after discontinuing TKI has increasingly become a new goal for CML treatment. However, TKI only "control" CML, and relapse after discontinuation has become a key factor hindering patient access to attempt TFR. In this study, we reviewed studies on TKI discontinuation, including both first and second-generation TKI. We also reviewed predictors of relapse, new monitoring methods, and strategies targeting leukemic stem cells.
    Keywords:  chronic myeloid leukemia; discontinuation; leukemia stem cells; treatment-free remission; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3389/fonc.2021.769730
  9. Blood Rev. 2021 Nov 03. pii: S0268-960X(21)00111-9. [Epub ahead of print] 100905
    A review of FLT3 inhibitors in acute myeloid leukemia.
    Jennifer C Zhao, Sonal Agarwal, Hiba Ahmad, Kejal Amin, Jan Philipp Bewersdorf, Amer M Zeidan.
      FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations and their prognostic implications, multiple FLT3-targeted molecules have been evaluated. Midostaurin is approved in the U.S. and Europe for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy based on data from the RATIFY study. Gilteritinib is approved for relapsed or refractory FLT3 mutated AML as monotherapy based on the ADMIRAL study. Although significant progress has been made in the treatment of AML with FLT3-targeting, many challenges remain. Several drug resistance mechanisms have been identified, including clonal selection, stromal protection, FLT3-associated mutations, and off-target mutations. The benefit of FLT3 inhibitor maintenance therapy, either post-chemotherapy or post-transplant, remains controversial, although several studies are ongoing.
    Keywords:  Acute myeloid leukemia; Crenolanib; FLT3; Gilteritinib; Midostaurin; Quizartinib
    DOI:  https://doi.org/10.1016/j.blre.2021.100905
  10. Blood. 2021 Nov 15. pii: blood.2021011802. [Epub ahead of print]
    MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common β Chain Cytokine Receptor Endocytosis.
    Helong Zhao, Anthony D Pomicter, Anna M Eiring, Anca Franzini, Jonathan Ahmann, Jae-Yeon Hwang, Anna V Senina, Bret Helton, Siddharth M Iyer, Dongqing Yan, Jamshid S Khorashad, Matthew S Zabriskie, Anupriya Agarwal, Hannah M Redwine, Amber D Bowler, Phillip M Clair, Shannon K McWeeney, Brian J Druker, Jeffrey W Tyner, Derek L Stirewalt, Vivian G Oehler, Sooryanarayana Varambally, Kristofer C Berrett, Jeffrey M Vahrenkamp, Jason Gertz, Katherine E Varley, Jerald Radich, Michael W Deininger.
      The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells, but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase. Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor, but promotes endocytosis of common β chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhance leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and blast phase CML. Promoting MS4A3 re-expression or delivery of ectopic MS4A3 may help eliminating LSPCs in vivo.
    DOI:  https://doi.org/10.1182/blood.2021011802
  11. Adv Ther. 2021 Nov 16.
    The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia.
    Valeria Santini, Michael Lübbert, Agnieszka Wierzbowska, Gert J Ossenkoppele.
      Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in the treatment of acute myeloid leukemia (AML). Decitabine inhibits DNA methyltransferases, causing DNA hypomethylation, and limiting the transcription of tumor suppressor genes, leading to gene silencing. Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy. The initial authorization in 2012 was based on the results of the open-label, randomized, multicenter phase 3 DACO-016 trial, and supported by data from the supportive phase 2 open-label DACO-017 trial. Compared with standard care, decitabine significantly improved overall survival, event-free survival, progression-free survival, and response rate. Decitabine was generally well tolerated, offering a valuable treatment option in patients with AML irrespective of age, especially for patients achieving a complete response. Several observational "real-life" studies confirmed these results. In contrast to standard chemotherapy, the presence of adverse-risk karyotypes or TP53 mutations does not negatively impact sensitivity to hypomethylating therapy albeit with lower durability. Data suggest a potential positive effect of decitabine in patients with monosomal karyotype-positive AML. For the time being, decitabine is an appropriate option as monotherapy for patients with AML who are unfit to receive more intensive combination therapies, but emerging data suggest that decitabine-based doublet or triplet combinations may be future treatment options for patients with AML.
    Keywords:  Acute myeloid leukemia; Decitabine; Elderly; HMAs; Hypomethylating agents
    DOI:  https://doi.org/10.1007/s12325-021-01948-8
  12. Leukemia. 2021 Nov 13.
    Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries.
    Christian Récher, Christoph Röllig, Emilie Bérard, Sarah Bertoli, Pierre-Yves Dumas, Suzanne Tavitian, Michael Kramer, Hubert Serve, Martin Bornhäuser, Uwe Platzbecker, Carsten Müller-Tidow, Claudia D Baldus, David Martínez-Cuadrón, Josefina Serrano, Pilar Martínez-Sánchez, Eduardo Rodríguez Arbolí, Cristina Gil, Juan Bergua, Teresa Bernal, Adolfo de la Fuente Burguera, Eric Delabesse, Audrey Bidet, Arnaud Pigneux, Pau Montesinos.
      The outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7-11.6) and 9.2 months (95% CI: 8.3-10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P < 0.0001). Treatment effect on overall survival was time-dependent. The Royston and Parmar model showed that patients treated with hypomethylating agents had a significantly lower risk of death before 1.5 months of follow-up; no significant difference between 1.5 and 4.0 months, whereas patients treated with intensive chemotherapy had a significantly better overall survival from four months after start of therapy. This study shows that intensive chemotherapy remains a valuable option associated with a better long-term survival in older AML patients.
    DOI:  https://doi.org/10.1038/s41375-021-01425-9
  13. Blood. 2021 Nov 17. pii: blood.2021014052. [Epub ahead of print]
    DNMT3A Overgrowth Syndrome is associated with the development of hematopoietic malignancies in children and young adults.
    Margaret A Ferris, Amanda M Smith, Sharon E Heath, Eric J Duncavage, Matthew J Oberley, David Freyer, Robert Wynn, Sofia Douzgou, John M Maris, Anne F Reilly, Melinda Wu, Florence Choo, Roel B Fiets, Saskia Koene, David H Spencer, Chrstopher A Miller, Marwan Shinawi, Timothy J Ley.
      DNMT3A Overgrowth Syndrome (DOS, also known as Tatton-Brown Rahman Syndrome/TBRS) is one of several overgrowth syndromes with complex phenotypes caused by constitutional mutations in genes encoding epigenetic regulators. The clinical features of DOS are variable but include overgrowth (tall stature and/or obesity) and intellectual disability. DNMT3A is essential for de novo DNA methylation and plays an important role in hematopoiesis. Somatic mutations in DNMT3A are among the most common initiating mutations in normal karyotype acute myeloid leukemia (AML) patients and in elderly people with clonal hematopoiesis. The natural history of DOS has not been fully explored since the first description of this rare condition in 2014. Because of the association of somatic DNMT3A mutations and leukemia development, we assessed information from the ~200 known DOS patients world-wide and were able to document eight with hematologic malignancies. Based on this prevalence, we suggest DOS is a cancer predisposition syndrome, especially for hematologic malignancies. Using recommendations from an expert panel, we suggest DOS patients should be prospectively monitored for hematologic malignancies, which may allow for early intervention and permit its natural history to be better defined.
    DOI:  https://doi.org/10.1182/blood.2021014052
  14. J Hematol Oncol. 2021 Nov 13. 14(1): 193
    A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia.
    Shilin Xu, Meichen Zhang, Xiaocui Fang, Jie Meng, Haiyan Xing, Doudou Yan, Jian Liu, Yanlian Yang, Tao Wen, Weiqi Zhang, Jianxiang Wang, Chen Wang, Haiyan Xu.
      Acute myeloid leukemia (AML) is a common malignant heterogeneous hematopoietic disease with very low average 5-year survival rate due to the refractory feature and high rate of relapse. CD123 is highly expressed on multiple types of AML cells, especially leukemia stem cells, and closely associated with the poor prognosis of AML. Aiming to meet the urgent demand to targeted therapeutics for the refractory AML patients, herein we synthesize a CD123 antagonistic peptide (PO-6) loaded in nanomicelles (mPO-6), and investigated its therapeutic effect and pharmacokinetics on a lab-established refractory AML mice model (AE & CKITD816V). It is shown that the PO-6 can effectively bind to the CD123+ AML cells and the micellar formulation mPO-6 increases the dissolution stability and the specific binding capacity. When injected intravenously, mPO-6 significantly prolongs the survival of the refractory AML mice by interfering CD123/IL-3 axis, evidenced by the down regulation of phosphorylation of STAT5 and PI3K/AKT and the inhibition of activated NF-κB in the nucleus, as well as by the analysis results of next generation RNA-sequencing (RNA-seq) with the bone marrow of the AML mice. The antagonistic effect leads to the significantly reduction of AML cells infiltration in the bone marrow of the AML mice. In conclusion, mPO-6 could provide a potent antagonistic therapeutic approach for targeted treatment of AML.
    Keywords:  Acute myeloid leukemia; Antagonistic peptide; CD123; Micelle; Targeting
    DOI:  https://doi.org/10.1186/s13045-021-01206-y
  15. PLoS One. 2021 ;16(11): e0259197
    A B-cell developmental gene regulatory network is activated in infant AML.
    Hamid Bolouri, Rhonda Ries, Laura Pardo, Tiffany Hylkema, Wanding Zhou, Jenny L Smith, Amanda Leonti, Michael Loken, Jason E Farrar, Timothy J Triche, Soheil Meshinchi.
      Infant Acute Myeloid Leukemia (AML) is a poorly-addressed, heterogeneous malignancy distinguished by surprisingly few mutations per patient but accompanied by myriad age-specific translocations. These characteristics make treatment of infant AML challenging. While infant AML is a relatively rare disease, it has enormous impact on families, and in terms of life-years-lost and life limiting morbidities. To better understand the mechanisms that drive infant AML, we performed integrative analyses of genome-wide mRNA, miRNA, and DNA-methylation data in diagnosis-stage patient samples. Here, we report the activation of an onco-fetal B-cell developmental gene regulatory network in infant AML. AML in infants is genomically distinct from AML in older children/adults in that it has more structural genomic aberrations and fewer mutations. Differential expression analysis of ~1500 pediatric AML samples revealed a large number of infant-specific genes, many of which are associated with B cell development and function. 18 of these genes form a well-studied B-cell gene regulatory network that includes the epigenetic regulators BRD4 and POU2AF1, and their onco-fetal targets LIN28B and IGF2BP3. All four genes are hypo-methylated in infant AML. Moreover, micro-RNA Let7a-2 is expressed in a mutually exclusive manner with its target and regulator LIN28B. These findings suggest infant AML may respond to bromodomain inhibitors and immune therapies targeting CD19, CD20, CD22, and CD79A.
    DOI:  https://doi.org/10.1371/journal.pone.0259197
  16. Blood Cancer Discov. 2021 Nov;2(6): 616-629
    Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.
    Joshua F Zeidner, Benjamin G Vincent, Anastasia Ivanova, Dominic Moore, Karen P McKinnon, Alec D Wilkinson, Rupkatha Mukhopadhyay, Francesco Mazziotta, Hanna A Knaus, Matthew C Foster, Catherine C Coombs, Katarzyna Jamieson, Hendrik Van Deventer, Jonathan A Webster, Gabrielle T Prince, Amy E DeZern, B Douglas Smith, Mark J Levis, Nathan D Montgomery, Leo Luznik, Jonathan S Serody, Ivana Gojo.
      Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab.Significance: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0070
  17. Blood Cancer J. 2021 Nov 16. 11(11): 182
    Activated naïve γδ T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia.
    Yu-Cheng Chang, Yi-Hao Chiang, Kate Hsu, Chih-Kuang Chuang, Chen-Wei Kao, Yi-Fang Chang, Ming-Chih Chang, Ken-Hong Lim, Hung-I Cheng, Yen-Ning Hsu, Caleb G Chen.
      Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the frontline treatments in chronic myeloid leukemia (CML). Growing evidence has shown that TKIs also enhance immunity. Since gamma-delta T (γδT) cells possess the potent anticancer capability, here we investigated the potential involvement of γδT cells in TKI treatments for CML. We characterized γδT cells isolated from chronic-phase CML patients before and during TKI treatments. γδT expression increased significantly in CML patients who achieved major molecular response (MMR) and deep molecular response (DMR). Their Vδ2 subset of γδT also expanded, and increased expression of activating molecules, namely IFN-γ, perforin, and CD107a, as well as γδT cytotoxicity. Mechanistically, TKIs augmented the efflux of isopentenyl pyrophosphate (IPP) from CML cells, which stimulated IFN-γ production and γδT expansion. Notably, the size of the IFN-γ+ naïve γδT population in TKI-treated CML patients was strongly correlated with their rates to reach DMR and with the duration on DMR. Statistical analysis suggests that a cutoff of 7.5% IFN-γ+ naïve subpopulation of γδT in CML patients could serve as a determinant for MR4.0 sustainability. Our results highlight γδT cells as a positive regulator for TKI responses in CML patients.
    DOI:  https://doi.org/10.1038/s41408-021-00572-7
  18. Blood Cancer Discov. 2021 Nov;2(6): 648-665
    NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.
    Rebecca M Richards, Feifei Zhao, Katherine A Freitas, Kevin R Parker, Peng Xu, Amy Fan, Elena Sotillo, Mads Daugaard, Htoo Zarni Oo, Jie Liu, Wan-Jen Hong, Poul H Sorensen, Howard Y Chang, Ansuman T Satpathy, Robbie G Majzner, Ravindra Majeti, Crystal L Mackall.
      Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines.Significance: CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.See related commentary by Velasquez and Gottschalk, p. 559. This article is highlighted in the In This Issue feature, p. 549.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0208
  19. Blood Cancer Discov. 2021 Nov;2(6): 586-599
    Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators.
    Maarten Fornerod, Jing Ma, Sanne Noort, Yu Liu, Michael P Walsh, Lei Shi, Stephanie Nance, Yanling Liu, Yuanyuan Wang, Guangchun Song, Tamara Lamprecht, John Easton, Heather L Mulder, Donald Yergeau, Jacquelyn Myers, Jennifer L Kamens, Esther A Obeng, Martina Pigazzi, Marie Jarosova, Charikleia Kelaidi, Sophia Polychronopoulou, Jatinder K Lamba, Sharyn D Baker, Jeffrey E Rubnitz, Dirk Reinhardt, Marry M van den Heuvel-Eibrink, Franco Locatelli, Henrik Hasle, Jeffery M Klco, James R Downing, Jinghui Zhang, Stanley Pounds, C Michel Zwaan, Tanja A Gruber.
      Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3-ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell-like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification.Significance: Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes. This article is highlighted in the In This Issue feature, p. 549.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0049
  20. J Clin Oncol. 2021 Nov 18. JCO2102286
    Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation.
    Christopher J Gibson, Haesook T Kim, Lin Zhao, H Moses Murdock, Bryan Hambley, Alana Ogata, Rafael Madero-Marroquin, Shiyu Wang, Lisa Green, Mark Fleharty, Tyler Dougan, Chi-An Cheng, Brendan Blumenstiel, Carrie Cibulskis, Junko Tsuji, Madeleine Duran, Christopher D Gocke, Joseph H Antin, Sarah Nikiforow, Amy E DeZern, Yi-Bin Chen, Vincent T Ho, Richard J Jones, Niall J Lennon, David R Walt, Jerome Ritz, Robert J Soiffer, Lukasz P Gondek, R Coleman Lindsley.
      PURPOSE: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.PATIENTS AND METHODS: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.
    RESULTS: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.
    CONCLUSION: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.
    DOI:  https://doi.org/10.1200/JCO.21.02286
  21. Leukemia. 2021 Nov 15.
    Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9.
    Friederike Christen, Raphael Hablesreiter, Kaja Hoyer, Cornelius Hennch, Antje Maluck-Böttcher, Angela Segler, Annett Madadi, Mareike Frick, Lars Bullinger, Franziska Briest, Frederik Damm.
      To investigate clonal hematopoiesis associated gene mutations in vitro and to unravel the direct impact on the human stem and progenitor cell (HSPC) compartment, we targeted healthy, young hematopoietic progenitor cells, derived from umbilical cord blood samples, with CRISPR/Cas9 technology. Site-specific mutations were introduced in defined regions of DNMT3A, TET2, and ASXL1 in CD34+ progenitor cells that were subsequently analyzed in short-term as well as long-term in vitro culture assays to assess self-renewal and differentiation capacities. Colony-forming unit (CFU) assays revealed enhanced self-renewal of TET2 mutated (TET2mut) cells, whereas ASXL1mut as well as DNMT3Amut cells did not reveal significant changes in short-term culture. Strikingly, enhanced colony formation could be detected in long-term culture experiments in all mutants, indicating increased self-renewal capacities. While we could also demonstrate preferential clonal expansion of distinct cell clones for all mutants, the clonal composition after long-term culture revealed a mutation-specific impact on HSPCs. Thus, by using primary umbilical cord blood cells, we were able to investigate epigenetic driver mutations without confounding factors like age or a complex mutational landscape, and our findings provide evidence for a direct impact of clonal hematopoiesis-associated mutations on self-renewal and clonal composition of human stem and progenitor cells.
    DOI:  https://doi.org/10.1038/s41375-021-01469-x
  22. Br J Haematol. 2021 Nov 19.
    Gemtuzumab ozogamicin in (KMT2A)-rearranged adult acute myeloid leukaemia (AML) in the UK Medical Research Council AML15 and AML16 trials.
    Richard Dillon, Robert K Hills, Alan K Burnett, Nigel H Russell.
      
    DOI:  https://doi.org/10.1111/bjh.17943
  23. Leuk Res. 2021 Oct 28. pii: S0145-2126(21)01737-9. [Epub ahead of print]111 106736
    Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.
    Selina M Luger, Victoria X Wang, Jacob M Rowe, Mark R Litzow, Elisabeth Paietta, Rhett P Ketterling, Hillard Lazarus, Witold B Rybka, Michael D Craig, Judith Karp, Brenda W Cooper, Adel Z Makary, Lynne S Kaminer, Frederick R Appelbaum, Richard A Larson, Martin S Tallman.
      PURPOSE: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse.PATIENTS AND METHODS: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients.
    RESULTS: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001).
    CONCLUSION: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.
    Keywords:  AML; Maintenance; Tipifarnib
    DOI:  https://doi.org/10.1016/j.leukres.2021.106736
  24. PLoS One. 2021 ;16(11): e0255706
    Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype.
    Ling Tian, Monique Chavez, Gue Su Chang, Nichole M Helton, Casey D S Katerndahl, Christopher A Miller, Lukas D Wartman.
      Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.
    DOI:  https://doi.org/10.1371/journal.pone.0255706
  25. Blood Adv. 2021 Nov 15. pii: bloodadvances.2021005224. [Epub ahead of print]
    Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen.
    Birgitta Versluijs, Coco C H De Koning, Arjan C Lankester, Stefan Nierkens, Wouter J Kollen, Dorine Bresters, Caroline A Lindemans, Jaap Jan Boelens, Marc Bierings.
      We prospectively studied CloFluBu-conditioning in allogeneic Hematopoietic Cell Therapy (HCT) for lymphoid- and myeloid malignancies, and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate anti-leukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. Primary endpoint was Event Free Survival (EFS). Secondary endpoints were Overall Survival (OS), Graft-versus-Host-Disease (GvHD)-Relapse-Free Survival (GRFS), Treatment Related Mortality (TRM), Cumulative Incidence of Relapse (CIR), acute and chronic GvHD, and veno-occlusive disease (VOD). Cox Proportional Hazard- and Fine and Gray competing-risk models were used for data analysis. 155 Children were included; 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). Median age was 9.7 (0.5-18.6) years. Estimated 2-yr EFS was 72.0% ± 6.0 in ALL, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD III-IV at 6 months was 12.3% ± 2.7, extensive chronic GvHD at 2-yr was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005224
  26. Stem Cell Reports. 2021 Nov 10. pii: S2213-6711(21)00547-6. [Epub ahead of print]
    CD62L expression level determines the cell fate of myeloid progenitors.
    Yusuke Ito, Fumio Nakahara, Yuki Kagoya, Mineo Kurokawa.
      Hematopoietic cells differentiate through several progenitors in a hierarchical manner, and recent single-cell analyses have revealed substantial heterogeneity within each progenitor. Although common myeloid progenitors (CMPs) are defined as a multipotent cell population that can differentiate into granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs), and GMPs generate neutrophils and monocytes, these myeloid progenitors must contain some lineage-committed progenitors. Through gene expression analysis at single-cell levels, we identified CD62L as a marker to reveal the heterogeneity. We confirmed that CD62L-negative CMPs represent "bona fide" CMPs, whereas CD62L-high CMPs are mostly restricted to GMP potentials both in mice and humans. In addition, we identified CD62L-negative GMPs as the most immature subsets in GMPs and Ly6C+CD62L-intermediate and Ly6C+CD62L-high GMPs are skewed to neutrophil and monocyte differentiation in mice, respectively. Our findings contribute to more profound understanding about the mechanism of myeloid differentiation.
    Keywords:  CD62L; common myeloid progenitor; granulocyte-monocyte progenitor
    DOI:  https://doi.org/10.1016/j.stemcr.2021.10.012
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