bims-tremyl 2022-10-09 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2022–10–09
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.
RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS.
A high hematopoietic cell transplantation comorbidity Index (HCT-CI) does not impair outcomes after non-myeloablative allogeneic stem cell transplantation in acute myeloid leukemia patients 60 years or older.
Pathogenic Mechanisms in Acute Myeloid Leukemia.
TP53 or Not TP53: That is the Question.
Role of ASXL1 in Hematopoiesis and Myeloid Diseases.
Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC).
Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis.
Subclones of bone marrow CD34+ cells in acute myeloid leukemia at diagnosis confer responses of patients to induction chemotherapy.
Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia.
High Molecular and Cytogenetic Risk in Myelofibrosis Does Not Benefit From Higher Intensity Conditioning Before Hematopoietic Cell Transplantation: An International Collaborative Analysis.
Machine Learning-Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine.
HOXA9 has the hallmarks of a biological switch with implications in blood cancers.
Dangerous Liaisons between Tet2 Mutation, Inflammatory Monocytes, and Leukemogenesis.
MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.
Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors.
Therapy related myeloid neoplasms following PARP inhibitors: real-life experience.
Five-day versus 7-day treatment regimen with azacitidine in lower risk myelodysplastic syndrome: A phase 2, multicenter, randomized trial.
GATA1 controls numbers of hematopoietic progenitors and their response to autoimmune neuroinflammation.
Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.
A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.
Anagrelide in essential thrombocythemia: Efficacy and long-term consequences in young patient population.
Relevance of infections on the outcomes of patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia treated with hypomethylating agents: a cohort study from the GESMD.

Blood. 2022 Oct 07. pii: blood.2022016580. [Epub ahead of print]

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.

Hongxia Chen, Yunpeng Bai, Michihiro Kobayashi, Shiyu Xiao, Wenjie Cai, Sergio Barajas, Sisi Chen, Jinmin Miao, Frederick Nguele Meke, Sasidhar Vemula, James Ropa, James Croop, H Scott Boswell, Jun Wan, Yuzhi Jia, Huiping Liu, Loretta Li, Jessica K Altman, Elizabeth A Eklund, Peng Ji, Wei Tong, Hamid Band, Danny Huang, Leonidas C Platanias, Zhong-Yin Zhang, Yan Liu.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FLT3 is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. While protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared to normal human hematopoietic stem and progenitor cells (HSPCs), the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-ITD-driven leukemia and extend the survival of leukemic mice. Further, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.

DOI: https://doi.org/10.1182/blood.2022016580
Blood Adv. 2022 Oct 07. pii: bloodadvances.2022007804. [Epub ahead of print]

RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS.

Yi-Jou Huang, Jia-Yu Chen, Ming Yan, Amanda G Davis, Sayuri Miyauchi, Liang Chen, Yajing Hao, Sigrid Katz, Rafael Bejar, Omar Abdel-Wahab, Xiang-Dong Fu, Dong-Er Zhang.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies with propensity to progress to acute myeloid leukemia (AML). Causal mutations in multiple classes of genes have been identified in MDS patients with some patients harboring more than one mutation. Interestingly, double mutations tend to occur in different classes, rather than the same class of genes, as exemplified by frequent co-occurring mutations in the transcription factor RUNX1 and the splicing factor SRSF2. This prototypic double mutant provides an opportunity to understand how their divergent functions in transcription and post-transcriptional regulation may be altered to jointly promote MDS. Here we report a mouse model in which Runx1 knockout was combined with the Srsf2 P95H mutation to cause multi-lineage hematopoietic defects. Besides their additive and synergistic effects, we also unexpectedly noted a degree of antagonizing activity of single mutations in specific hematopoietic progenitors. To uncover the mechanism, we further developed a cellular model using human K562 cells and performed parallel gene expression and splicing analyses in both human and murine contexts. Strikingly, while RUNX1 deficiency was responsible for altered transcription in both single and double mutants, it also induced dramatic changes in global splicing, as seen with mutant SRSF2, and only their combination induced mis-splicing of genes selectively enriched in the DNA damage response and cell cycle checkpoint pathways. Collectively, these data reveal the convergent impact of a prototypic MDS-associated double mutant on RNA processing and suggest that aberrant DNA damage repair and cell cycle regulation critically contribute to MDS development.

DOI: https://doi.org/10.1182/bloodadvances.2022007804
Bone Marrow Transplant. 2022 Oct 04.

A high hematopoietic cell transplantation comorbidity Index (HCT-CI) does not impair outcomes after non-myeloablative allogeneic stem cell transplantation in acute myeloid leukemia patients 60 years or older.

Donata Backhaus, Dominic Brauer, Rosmarie Pointner, Lara Bischof, Vladan Vucinic, Georg-Nikolaus Franke, Dietger Niederwieser, Uwe Platzbecker, Madlen Jentzsch, Sebastian Schwind.

For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. The introduction of less toxic non-myeloablative conditioning (NMA) regimes enabled older and/or comorbid patients to be consolidated with an allogeneic HSCT. While the hematopoietic cell transplantation comorbidity index (HCT-CI) predicted outcomes in many younger patient cohorts its impact in older AML patients receiving NMA-HSCT remains unknown. Here we analyzed 289 AML patients 60 years or older (median age 66, range 60-77 years) undergoing NMA-HSCT (2 or 3 Gray total body irradiation and 3 days of fludarabine 30 mg/m2). HCT-CI risk was low, intermediate, or high in 36%, 31%, and 33% of patients, respectively. Non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and overall survival (OS) did not differ between HCT-CI groups. The HCT-CI also did not impact outcomes when considering the European LeukemiaNet 2017 risk at diagnosis or the measurable residual disease (MRD) status at HSCT. Notably, MRD-negative older NMA-transplanted AML patients had a beneficial OS of 49% after 5 years. Since a higher HCT-CI did not impair outcomes, age or comorbidities per se should not impede NMA-HSCT, presenting a feasible consolidation option for this group of AML patients.

DOI: https://doi.org/10.1038/s41409-022-01833-0
Curr Treat Options Oncol. 2022 Oct 03.

Pathogenic Mechanisms in Acute Myeloid Leukemia.

Sohini Chakraborty, Christopher Y Park.

   OPINION STATEMENT: Acute myeloid leukemia (AML) is the most common form of leukemia in adults, leading to the highest number of annual leukemia-associated deaths in the USA. Although most AML patients initially enter remission following induction therapy, most eventually relapse, underscoring the unmet need for more effective therapies. In recent years, novel high-throughput sequencing techniques, and mouse and human models of disease have increased our understanding of the molecular mechanisms that lead to AML. Leukemogenic mechanisms can be broadly classified into two types-cell-intrinsic and cell-extrinsic. Cell-intrinsic mechanisms include an array of genetic and epigenetic alterations that lead to dysregulated gene expression and function in hematopoietic stem/progenitor cells, leading to their increased fitness and ultimately, malignant transformation. Extrinsic mechanisms include both hematopoietic and non-hematopoietic stromal components of the leukemic microenvironment that interact with pre-leukemic and leukemic clones to promote their survival, self-renewal, and/or resistance to therapy. Through the individual and concerted action of these factors, pre-leukemic clones acquire the changes necessary for leukemic transformation. In addition, following therapy, specific leukemic clones are selected for that eventually re-initiate disease. Improving our understanding of these cell-intrinsic and cell-extrinsic mechanisms will provide novel opportunities to treat AML as well as prevent the development of disease.

Keywords:  Acute myeloid leukemia (AML); Bone marrow (BM) microenvironment; Clonal hematopoiesis (CH); Epigenetic mechanisms; Germline mutations; Hematopoietic stem/progenitor cells (HSPCs); Leukemia stem cells (LSCs); Noncoding RNAs; Somatic mutations

DOI:  https://doi.org/10.1007/s11864-022-01021-8
Clin Cancer Res. 2022 Oct 05. pii: CCR-22-2664. [Epub ahead of print]

TP53 or Not TP53: That is the Question.

Steven D Green, Joshua F Zeidner.

Azacitidine and venetoclax is a standard frontline regimen for newly diagnosed unfit AML patients. In a pooled subset analysis, TP53-mutated AML with poor-risk cytogenetics do not appear to benefit from the addition of venetoclax to azacitidine. This has clinical implications as these patients should be preferentially treated with alternative regimens.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2664
Exp Hematol. 2022 Sep 29. pii: S0301-472X(22)00699-3. [Epub ahead of print]

Role of ASXL1 in Hematopoiesis and Myeloid Diseases.

Xin Gao, Xiaona You, Nathalie Droin, Lauren G Banaszak, Jane Churpek, Eric Padron, Klaus Geissler, Eric Solary, Mrinal M Patnaik, Jing Zhang.

Next-generation sequencing technology (NGS), including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.

DOI: https://doi.org/10.1016/j.exphem.2022.09.003
Eur J Med Chem. 2022 Sep 26. pii: S0223-5234(22)00694-8. [Epub ahead of print]243 114792

Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC).

Eva Řezníčková, Soňa Krajčovičová, Miroslav Peřina, Markéta Kovalová, Miroslav Soural, Vladimír Kryštof.

  Oncogenic mutations in gene encoding FLT3 kinase are often detected in acute myeloid leukaemia (AML) patients, and several potent kinase inhibitors have been developed. However, the FLT3 inhibitor treatment often leads to the resistance development and subsequent relapse. Targeted degradation of oncogenic protein kinases has emerged as a feasible pharmacological strategy, providing more robust effect over traditional competitive inhibitors. Based on previously developed competitive inhibitor of FLT3 and CDK9, we have designed and prepared a novel pomalidomide-based PROTAC. A series of biochemical and cellular experiments showed selectivity towards FLT3-ITD bearing AML cells and confirmed proteasome-dependent mechanism of action. Dual FLT3-ITD and CDK9 protein degradation resulted in the block of FLT3-ITD downstream signalling pathways, apoptosis activation and cell cycle arrest of FLT3-ITD AML cells. Moreover, transcriptional repression caused by CDK9 degradation significantly reduced expression of crucial genes involved in AML pathogenesis. The obtained results indicate the beneficial impact of simultaneous FLT3-ITD/CDK9 degradation for AML therapy.

Keywords:  Acute myeloid leukaemia; CDK9; FLT3; Proteolysis targeting chimera (PROTAC)

DOI:  https://doi.org/10.1016/j.ejmech.2022.114792
J Exp Clin Cancer Res. 2022 Oct 07. 41(1): 294

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis.

Kanak Joshi, Lei Zhang, Peter Breslin S J, Ameet R Kini, Jiwang Zhang.

  The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40-50% of cases of TET2-mutant (TET2MT) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2MT collaborates with co-occurring mutations to promote malignant transformation. In TET2MT tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2MT hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2MT malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2MT hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals.

Keywords:  Concurring mutations; Differentiation; HSPCs; Leukemia; MDS; Self-renewal; TET2

DOI:  https://doi.org/10.1186/s13046-022-02496-x
Cancer. 2022 Oct 05.

Subclones of bone marrow CD34+ cells in acute myeloid leukemia at diagnosis confer responses of patients to induction chemotherapy.

Ruinan Jia, Min Ji, Guosheng Li, Yuan Xia, Shouhui Guo, Peng Li, Yanping Sun, Fei Lu, Jingru Zhang, Shaolei Zang, Shuxin Yan, Jingjing Ye, Fuzhong Xue, Daoxin Ma, Tao Sun, Chunyan Ji.

   BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding.
METHODS: In our study, using single-cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34+ cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry.
RESULTS: We established a landscape for AML CD34+ cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1high LGALS1high S100Ashigh showing features of granulocyte-monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34+ CD52+ or CD34+ CD74+ DAP12+ were related to good response to induction therapy, showing characteristics of hematopoietic stem cells.
CONCLUSION: Our study indicates the subclones of CD34+ cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy.

Keywords:  Acute myeloid leukemia; CD34+cell; Heterogeneity; Induction chemotherapy; Single-cell RNA-sequencing

DOI:  https://doi.org/10.1002/cncr.34481
iScience. 2022 Oct 21. 25(10): 105139

Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia.

Bianca Y Pingul, Hua Huang, Qingzhou Chen, Fatemeh Alikarami, Zhen Zhang, Jun Qi, Kathrin M Bernt, Shelley L Berger, Zhendong Cao, Junwei Shi.

  Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed transcription factor (TF) vulnerabilities in leukemia and uncovered TF clusters that exhibit context-specific vulnerabilities within and between different subtypes of leukemia. Among these TF clusters, we demonstrated that acute myeloid leukemia (AML) with high IRF8 expression was addicted to MEF2D. MEF2D and IRF8 form an autoregulatory loop via direct binding to mutual enhancer elements. One important function of this circuit in AML is to sustain PU.1/MEIS1 co-regulated transcriptional outputs via stabilizing PU.1's chromatin occupancy. We illustrated that AML could acquire dependency on this circuit through various oncogenic mechanisms that results in the activation of their enhancers. In addition to forming a circuit, MEF2D and IRF8 can also separately regulate gene expression, and dual perturbation of these two TFs leads to a more robust inhibition of AML proliferation. Collectively, our results revealed a TF circuit essential for AML survival.

Keywords:  Biological sciences; Cancer; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2022.105139
Hemasphere. 2022 Oct;6(10): e784

High Molecular and Cytogenetic Risk in Myelofibrosis Does Not Benefit From Higher Intensity Conditioning Before Hematopoietic Cell Transplantation: An International Collaborative Analysis.

Nico Gagelmann, Rachel B Salit, Thomas Schroeder, Anita Badbaran, Christina Rautenberg, Victoria Panagiota, Christine Wolschke, Felicitas Thol, Bruno Cassinat, Marie Robin, Michael Heuser, Hans Christian Reinhardt, Bart L Scott, Nicolaus Kröger.

There is no direct evidence to recommend specific conditioning intensities in myelofibrosis undergoing allogeneic hematopoietic cell transplantation, especially in the molecular era. We aimed to compare outcomes of reduced intensity (RIC) or myeloablative conditioning (MAC) transplantation in myelofibrosis with molecular information. The study included 645 genetically annotated patients (with at least driver mutation status available), of whom 414 received RIC and 231 patients received MAC. The median follow-up time from transplantation was 6.0 years for RIC and 9.4 years for MAC. The 6-year overall survival rates for RIC and MAC were 63% (95% confidence interval [CI], 58%-68%) and 59% (95% CI, 52%-66%; P = 0.34) and progression-free survival was 52% (95% CI, 47%-57%) and 52% (95% CI, 45%-59%; P = 0.64). The 2-year cumulative incidence of nonrelapse mortality was 26% (95% CI, 21%-31%) for RIC and 29% (95% CI, 23%-34%) for MAC (P = 0.51). In terms of progression/relapse, the 2-year cumulative incidence was 10% (95% CI, 5%-19%) for RIC and 9% (95% CI, 4%-14%) for MAC (P = 0.46). Higher intensity conditioning did not seem to improve outcomes for higher-risk disease, according to mutational, cytogenetic, and clinical profile. In contrast, patients with reduced performance status, matched unrelated donors, and ASXL1 mutations appeared to benefit from RIC in terms of overall survival.

DOI: https://doi.org/10.1097/HS9.0000000000000784
JCO Clin Cancer Inform. 2022 Sep;6 e2200030

Machine Learning-Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine.

Nazmul Islam, Jamie S Reuben, Justin Dale, Jon Gutman, Christine M McMahon, Maria Amaya, Bruce Goodman, Joseph Toninato, Maura Gasparetto, Brett Stevens, Shanshan Pei, Austin Gillen, Sarah Staggs, Krysta Engel, Sarah Davis, Madelyne Hull, Elizabeth Burke, Lenny Larchick, Richard Zane, Grant Weller, Craig Jordan, Clay Smith.

PURPOSE: There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods.
PATIENTS AND METHODS: Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients.
RESULTS: A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3.
CONCLUSION: Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.

DOI: https://doi.org/10.1200/CCI.22.00030
Nat Commun. 2022 Oct 03. 13(1): 5829

HOXA9 has the hallmarks of a biological switch with implications in blood cancers.

Laure Talarmain, Matthew A Clarke, David Shorthouse, Lilia Cabrera-Cosme, David G Kent, Jasmin Fisher, Benjamin A Hall.

Blood malignancies arise from the dysregulation of haematopoiesis. The type of blood cell and the specific order of oncogenic events initiating abnormal growth ultimately determine the cancer subtype and subsequent clinical outcome. HOXA9 plays an important role in acute myeloid leukaemia (AML) prognosis by promoting blood cell expansion and altering differentiation; however, the function of HOXA9 in other blood malignancies is still unclear. Here, we highlight the biological switch and prognosis marker properties of HOXA9 in AML and chronic myeloproliferative neoplasms (MPN). First, we establish the ability of HOXA9 to stratify AML patients with distinct cellular and clinical outcomes. Then, through the use of a computational network model of MPN, we show that the self-activation of HOXA9 and its relationship to JAK2 and TET2 can explain the branching progression of JAK2/TET2 mutant MPN patients towards divergent clinical characteristics. Finally, we predict a connection between the RUNX1 and MYB genes and a suppressive role for the NOTCH pathway in MPN diseases.

DOI: https://doi.org/10.1038/s41467-022-33189-w
Cancer Discov. 2022 Oct 05. 12(10): 2234-2236

Dangerous Liaisons between Tet2 Mutation, Inflammatory Monocytes, and Leukemogenesis.

Eric M Pietras, James DeGregori.

Transgenic knockin mice expressing a common loss-of-function mutation in human TET2 exhibit aging-related accelerated myeloid leukemia development and skewing of myelopoiesis toward the production of proinflammatory MHC-IIhi monocytes that may contribute to disease. See related article by Yeaton et al., p. 2392 (2).

DOI: https://doi.org/10.1158/2159-8290.CD-22-0846
Cell Rep. 2022 Oct 04. pii: S2211-1247(22)01286-4. [Epub ahead of print]41(1): 111445

MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.

Michelle S Prew, Utsarga Adhikary, Dong Wook Choi, Erika P Portero, Joao A Paulo, Pruthvi Gowda, Amit Budhraja, Joseph T Opferman, Steven P Gygi, Nika N Danial, Loren D Walensky.

  MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.

Keywords:  BCL-2 family; CP: Cancer; CP: Metabolism; MCL-1; apoptosis; cancer; fatty acid oxidation; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2022.111445
Nat Cell Biol. 2022 Oct 06.

Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors.

Miguel Ganuza, Trent Hall, Jacquelyn Myers, Chris Nevitt, Raúl Sánchez-Lanzas, Ashley Chabot, Juan Ding, Emilia Kooienga, Claire Caprio, David Finkelstein, Guolian Kang, Esther Obeng, Shannon McKinney-Freeman.

Current dogma asserts that the foetal liver (FL) is an expansion niche for recently specified haematopoietic stem cells (HSCs) during ontogeny. Indeed, between embryonic day of development (E)12.5 and E14.5, the number of transplantable HSCs in the murine FL expands from 50 to about 1,000. Here we used a non-invasive, multi-colour lineage tracing strategy to interrogate the embryonic expansion of murine haematopoietic progenitors destined to contribute to the adult HSC pool. Our data show that this pool of fated progenitors expands only two-fold during FL ontogeny. Although Histone2B-GFP retention in vivo experiments confirmed substantial proliferation of phenotypic FL-HSC between E12.5 and E14.5, paired-daughter cell assays revealed that many mid-gestation phenotypic FL-HSCs are biased to differentiate, rather than self-renew, relative to phenotypic neonatal and adult bone marrow HSCs. In total, these data support a model in which the FL-HSC pool fated to contribute to adult blood expands only modestly during ontogeny.

DOI: https://doi.org/10.1038/s41556-022-00999-5
Clin Cancer Res. 2022 Oct 06. pii: CCR-22-1622. [Epub ahead of print]

Therapy related myeloid neoplasms following PARP inhibitors: real-life experience.

Vincent Marmouset, Justine Decroocq, Sylvain Garciaz, Gabriel Etienne, Amine Belhabri, Sarah Bertoli, Lauris Gastaud, Célestine Simand, Sylvain Chantepie, Madalina Uzunov, Alexis Genthon, Céline Berthon, Edmond Chiche, Pierre-Yves Dumas, Jacques Vargaftig, Géraldine Salmeron, Emilie Lemasle, Emmanuelle Tavernier, Jérémy Delage, Marion Loirat, Nadine Morineau, Félix Blanc-Durand, Patricia Pautier, Véronique Vergé, Nathalie Auger, Myrtille Thomas, Laetitia Stefani, Marion Lepelley, Thomas Boyer, Sylvain Thepot, Marie-Pierre Gourin, Pascal Bourquard, Matthieu Duchmann, Pierre-Marie Morice, Mauricette Michallet, Lionel Adès, Pierre Fenaux, Christian Récher, Hervé Dombret, Arnaud Pagès, Christophe Marzac, Alexandra Leary, Jean-Baptiste Micol.

PURPOSE: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).
EXPERIMENTAL DESIGN: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 ovarian cancer (OC) patients referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post PARPi among 37 t-MN post OC according to PARPi exposure. Finally, we described 69 t-MN post PARPi in a national cohort.
RESULTS: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among OC patients treated with PARPi. At time of hematological consultation, patients with t-MN had a longer PARPi exposure (9 months vs. 3, p= 0.01), lower platelet count (74 vs. 173 G/L, p=0.0005), and more cytopenias (2 vs. 1, p=0.0005). Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 germline mutation (61.5% vs. 0% p=0.03) but similar OS. In the national cohort, most t-MN post PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (IQR, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR 1.046, p=0.02), olaparib compared to others PARPi (HR 5.82, p=0.003) and AML (HR 2.485, p=0.01) were associated with shorter OS.
CONCLUSIONS: In a large series, we described a high incidence of t-MN post PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1622
Cancer. 2022 Oct 08.

Five-day versus 7-day treatment regimen with azacitidine in lower risk myelodysplastic syndrome: A phase 2, multicenter, randomized trial.

Silvia Park, So Yeon Park, Je-Hwan Lee, Eun-Ji Choi, Kyoo-Hyung Lee, Sung-Soo Yoon, Junshik Hong, Dong-Yeop Shin, Yoo-Jin Kim.

   BACKGROUND: Low-dose azacitidine (AZA) regimens, primarily 5-day AZA, have been used in lower risk myelodysplastic syndrome (LrMDS) but they have yet to be directly compared to the standard 7-day, uninterrupted dosing schedule.
METHOD: In this phase 2, multicenter, randomized trial, 55 patients with adult LrMDS (low and intermediate-1 risk by international prognostic scoring system [IPSS]) were randomly assigned and received either 5-day (n = 26) or 7-day (n = 29) AZA between March 2012 and August 2020. The trial was stopped prematurely because of the slow accrual of patients. The primary end point was the overall response rate (ORR) of the 5-day AZA as compared to that of the 7-day regimen.
RESULTS: Median patient age was 59 years, and IPSS intermediate-1 risk comprised the majority (81.8%). The median number of cycles in both arms was six. In the ITT subset (n = 53), in each of the 5-day and 7-day arms, the ORR of 48.0% and 39.3%, hematologic improvement of 44.0% and 39.3%, and RBC transfusion independence of 35.3% and 40.0% were observed respectively, and none of these findings were significantly different between the two arms. A cytogenetic response rate was significantly higher in the 7-day arm (8.3% and 53.8%, p = .027). Survival and adverse events were similar between the groups, although gastrointestinal toxicities, grade ≥3 thrombocytopenia, and febrile neutropenia were less frequent in the 5-day arm.
CONCLUSION: The 5-day AZA in LrMDS showed comparable efficacy to a 7-day regimen in terms of similar overall response and other outcomes, despite significantly higher rates of cytogenetic responses in the 7-day regimen.
LAY SUMMARY: Azacitidine (75 mg/m2 /day for 7 consecutive days per 28-day cycle) has shown survival benefit in patients with higher risk myelodysplastic syndrome (MDS). Although the use of azacitidine is less-well studied for lower risk MDS, it is generally accepted as a feasible option for lower risk MDS (LrMDS).

Keywords:  5-day regimen; 7-day standard regimen; azacitidine; dosing schedule; lower risk disease; myelodysplastic syndrome

DOI:  https://doi.org/10.1002/cncr.34492
Blood Adv. 2022 Oct 07. pii: bloodadvances.2022008234. [Epub ahead of print]

GATA1 controls numbers of hematopoietic progenitors and their response to autoimmune neuroinflammation.

Daniel Hwang, Larissa Lumi Watanabe Ishikawa, Maryam S Seyedsadr, Elisabeth Mari, Ezgi Ecem Kasimoglu, Ziver Sahin, Alexandra Boehm, Soohwa Jang, Javad Rasouli, Courtney Vaccaro, Michael Gonzalez, Hakon Hakonarson, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric.

GATA-binding factor 1 (GATA1) is a transcription factor that governs the development and function of multiple hematopoietic cell lineages. GATA1 is expressed in hematopoietic stem and progenitor cells (HSPCs) and is essential for erythroid lineage commitment, but if and what role it has in hematopoietic stem cell (HSC) biology and in the development of myeloid lineage cells is less clear. We initially set out to test the role of eosinophils in experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmunity, by using ΔdblGATA mice, which lack eosinophils due to deletion of the dblGATA enhancer to Gata1 that alters its expression. ΔdblGATA mice were resistant to EAE, but not because of the lack of eosinophils, suggesting that these mice have an additional defect. ΔdblGATA mice with EAE had fewer inflammatory myeloid cells than control mice, suggesting that the resistance to EAE is caused by a defect in myeloid cells. Naïve ΔdblGATA mice also had reduced frequency of blood CD11b+ myeloid cells, indicating a defect in myeloid cell production. Examination of HSPCs revealed fewer HSCs and myeloid cell progenitors in ΔdblGATA bone marrow, and competitive bone marrow chimera experiments showed a reduced capacity of ΔdblGATA bone marrow to reconstitute immune cells, suggesting that reduced numbers of ΔdblGATA HSPCs causes a functional deficit during inflammation. Taken together, our data show that GATA1 regulates the number of HSPCs, and that reduced GATA1 expression, due to dblGATA deletion, results in a diminished immune response following inflammatory challenge.

DOI: https://doi.org/10.1182/bloodadvances.2022008234
Ann Hematol. 2022 Oct 05.

Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.

Meunier Mathieu, Chloé Friedrich, Nicolas Ducrot, Johanna Zannoni, Tondeur Sylvie, Nelly Jerraya, Sophie Rousseaux, Florent Chuffart, Olivier Kosmider, Zoubida Karim, Sophie Park.

  In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.

Keywords:  Luspatercept; Myelodysplastic syndromes; PDX mice model; RAP-536

DOI:  https://doi.org/10.1007/s00277-022-04993-7
Science. 2022 Oct 07. 378(6615): 68-78

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Connor Yanchus, Kristen L Drucker, Thomas M Kollmeyer, Ricky Tsai, Warren Winick-Ng, Minggao Liang, Ahmad Malik, Judy Pawling, Silvana B De Lorenzo, Asma Ali, Paul A Decker, Matt L Kosel, Arijit Panda, Khalid N Al-Zahrani, Lingyan Jiang, Jared W L Browning, Chris Lowden, Michael Geuenich, J Javier Hernandez, Jessica T Gosio, Musaddeque Ahmed, Sampath Kumar Loganathan, Jacob Berman, Daniel Trcka, Kulandaimanuvel Antony Michealraj, Jerome Fortin, Brittany Carson, Ethan W Hollingsworth, Sandra Jacinto, Parisa Mazrooei, Lily Zhou, Andrew Elia, Mathieu Lupien, Housheng Hansen He, Daniel J Murphy, Liguo Wang, Alexej Abyzov, James W Dennis, Philipp G Maass, Kieran Campbell, Michael D Wilson, Daniel H Lachance, Margaret Wrensch, John Wiencke, Tak Mak, Len A Pennacchio, Diane E Dickel, Axel Visel, Jeffrey Wrana, Michael D Taylor, Gelareh Zadeh, Peter Dirks, Jeanette E Eckel-Passow, Liliana Attisano, Ana Pombo, Cristiane M Ida, Evgeny Z Kvon, Robert B Jenkins, Daniel Schramek.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

DOI: https://doi.org/10.1126/science.abj2890
Leuk Res. 2022 Sep 21. pii: S0145-2126(22)00188-6. [Epub ahead of print]123 106962

Anagrelide in essential thrombocythemia: Efficacy and long-term consequences in young patient population.

Maria Bieniaszewska, Patryk Sobieralski, Aleksandra Leszczyńska, Magdalena Dutka.

  According to the current treatment recommendations, anagrelide, an oral antiplatelet agent, is recommended as a second-line therapy for patients with high-risk essential thrombocythemia experiencing intolerance or refractoriness to first-line approach, such as hydroxyurea or pegylated interferon alpha-2a. If there is a need for introduction of cytoreductive treatment in young patients with a perspective of lifelong exposure, both the efficacy and long-term outcomes should be known. We present the analysis of 48 young patients, diagnosed with essential thrombocythemia below the age of 60, who were exposed to anagrelide treatment for over 10 years. Our observations show that the highest proportion of complete remissions without adverse events and disease progression is seen in the JAK2-mutated patients. By evaluating the changes in hemoglobin concentration and serum erythropoietin throughout the study, we were able to reveal the development of progressive anemia, resulting from diminished susceptibility to erythropoietin and unrelated to bone marrow fibrosis, in patients harboring CALR mutation. Additionally, occurrence of new bone marrow fibrosis was confirmed in seven JAK2-unmutated patients at the end of the study. In summary, in young patient population, we recommend limiting the use of anagrelide to JAK2-mutated subgroup, reducing exposure time and underline the importance of periodic monitoring for the presence of bone marrow fibrosis.

Keywords:  Anagrelide; Anemia; Erythropoietin; Essential thrombocythemia

DOI:  https://doi.org/10.1016/j.leukres.2022.106962
Ther Adv Hematol. 2022 ;13 20406207221127547

Relevance of infections on the outcomes of patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia treated with hypomethylating agents: a cohort study from the GESMD.

Laura Vilorio-Marqués, Christelle Castañón Fernández, Elvira Mora, Lorena Gutiérrez, Beatriz Rey Bua, Maria José Jiménez Lorenzo, Marina Díaz Beya, Miriam Vara Pampliega, Antonieta Molero, Joaquín Sánchez-García, Marisa Calabuig, Maria Teresa Cedena, Tzu Chen-Liang, Johana Alejandra Díaz Santa, Irene Padilla, Francisca Hernández, Rosana Díez, Pedro Asensi, Blanca Xicoy, Guillermo Sanz, David Valcárcel, María Diez-Campelo, Teresa Bernal.

   Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated.
Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting.
Design: Observational study.
Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection.
Results: The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26-1.84], p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3-8] versu 8 [5-16], p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09-1.88], p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14-3.96], p = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30-2.24], p < 0.001), and platelet count <50 × 109/l (HR = 1.69 [95% CI = 1.3-2.2], p < 0.001). BM blasts >20% (HR = 1.57 [95% CI = 1.19-2.01], p < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35-2.14], p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51-0.82], p < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996-0.998], p = 0.016) protected from it.
Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.

Keywords:  acute myeloid leukemia; hypomethylating agent; infection; myelodysplastic syndrome; treatment outcome

DOI:  https://doi.org/10.1177/20406207221127547