bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–01–31
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Genomic Characteristics and Prognostic Significance of Co-mutated ASXL1/SRSF2 Acute Myeloid Leukemia.
  2. Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence.
  3. CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
  4. Understanding of the crosstalk between normal residual hematopoietic stem cells and the leukemic niche in Acute Myeloid Leukemia.
  5. Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.
  6. Old dog, new trick: Type-I Interferon based treatment for acute myeloid leukaemia.
  7. The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia.
  8. Next-generation sequencing reveals gene mutations landscape and clonal evolution in patients with acute myeloid leukemia.
  9. Clinical responsiveness to All-trans Retinoic Acid is potentiated by LSD1 inhibition and associated with a quiescent transcriptome in myeloid malignancies.
  10. Late outcomes in survivors of childhood acute myeloid leukemia: a report from the St. Jude Lifetime Cohort Study.
  11. Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy.
  12. The transcriptional regulation of normal and malignant blood cell development.
  13. Genetic characterization of acute myeloid leukemia patients with mutations in IDH1/2 genes.
  14. Modeling and targeting of erythroleukemia by hematopoietic genome editing.
  15. Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis.
  16. Acute myeloid leukemia measurable residual disease detection by flow cytometry in peripheral blood vs bone marrow.
  17. DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes.
  18. Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function.
  19. Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1.
  20. Therapeutic approaches targeting splicing factor mutations in myelodysplastic syndromes and acute myeloid leukemia.
  21. PHGDH as a mechanism for resistance in metabolically-driven cancers.
  22. Primum non nocere: allo-HSCT for AML in CR1.
  23. Histone deacetylase 3 preferentially binds and collaborates with the transcription factor RUNX1 to repress AML1-ETO-dependent transcription in t(8;21) AML.
  1. Am J Hematol. 2021 Jan 27.
    Genomic Characteristics and Prognostic Significance of Co-mutated ASXL1/SRSF2 Acute Myeloid Leukemia.
    Daniel R Richardson, David M Swoboda, Dominic T Moore, Steven M Johnson, Onyee Chan, Jonathan Galeotti, Sonia Esparza, Mohammad O Hussaini, Hendrick Van Deventer, Matthew C Foster, Catherine C Coombs, Nathan D Montgomery, David A Sallman, Joshua F Zeidner.
      ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mut SRSF2mut AML and compared outcomes to patients with either ASXL1 (n=57) or SRSF2 (n=70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo versus s-AML (15.3 versus 6.4 months, respectively; p=0.04 on adjusted analysis). Compared to ASXL1mut SRSF2wt and ASXL1wt SRSF2mut , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (p=0.049), with a trend towards inferior OS (median OS = 7.0 vs. 11.5 vs. 10.9 months, respectively; p =0.10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs. 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mut SRSF2mut AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1mut SRSF2wt /ASXL1wt SRSF2mut with respect to etiology and leukemogenesis. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26110
  2. Cancer Discov. 2021 Jan 26. pii: candisc.1375.2020. [Epub ahead of print]
    Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence.
    Cihangir Duy, Meng Li, Matt Teater, Cem Meydan, Francine E Garrett-Bakelman, Tak C Lee, Christopher R Chin, Ceyda Durmaz, Kimihito C Kawabata, Eugen Dhimolea, Constantine S Mitsiades, Hartmut Doehner, Richard J D'Andrea, Michael W Becker, Elisabeth M Paietta, Christopher E Mason, Martin Carroll, Ari M Melnick.
      Acute myeloid leukemia (AML) patients frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1375
  3. Blood. 2021 Jan 07. pii: blood.2020006528. [Epub ahead of print]
    CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
    Roger Belizaire, Sebastian Hassan John Koochaki, Namrata D Udeshi, Alexis Vedder, Lei Sun, Tanya Svinkina, Christina Hartigan, Marie E McConkey, Veronica Kovalcik, Amanuel Bizuayehu, Caroline Stanclift, Monica Schenone, Steven A Carr, Eric Padron, Benjamin L Ebert.
      CBL encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and non-receptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10-20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein's E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, PIK3R1 recruitment, and downstream PI3K/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine-kinase binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies.
    DOI:  https://doi.org/10.1182/blood.2020006528
  4. Exp Hematol. 2021 Jan 23. pii: S0301-472X(21)00026-6. [Epub ahead of print]
    Understanding of the crosstalk between normal residual hematopoietic stem cells and the leukemic niche in Acute Myeloid Leukemia.
    Antoniana Batsivari, William Grey, Prof Dominique Bonnet.
      Acute myeloid leukemia (AML) is a heterogenous disease, yet clinically most patients present with pancytopenia resulting from bone marrow (BM) failure, predisposing them to life-threatening infections and bleeding. The mechanisms by which AML mediate hematopoietic suppression is not well known. Indeed, much effort has so far focussed on how AML remodels the bone marrow niche to make it a more permissive environment, with less focus on how the remodelled niche impacts normal hematopoietic cells. In this perspective, we present evidence of the key role of the bone marrow niche in suppressing HSCs during leukemic progression and provide perspectives on how future research in this topic may be exploited to provide treatments for one of the key complications of AML.
    Keywords:  AML; Bone marrow failure; Bone marrow niche; cross-talk
    DOI:  https://doi.org/10.1016/j.exphem.2021.01.004
  5. Blood Adv. 2021 Jan 26. 5(2): 513-526
    Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.
    Lucine Fahy, Julien Calvo, Sara Chabi, Laurent Renou, Charly Le Maout, Sandrine Poglio, Thierry Leblanc, Arnaud Petit, André Baruchel, Paola Ballerini, Irina Naguibneva, Rima Haddad, Marie-Laure Arcangeli, Frederic Mazurier, Francoise Pflumio, Benjamin Uzan.
      Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002832
  6. Mol Cancer Res. 2021 Jan 26. pii: molcanres.0871.2020. [Epub ahead of print]
    Old dog, new trick: Type-I Interferon based treatment for acute myeloid leukaemia.
    Abdullah Alsufyani, Rehab Alanazi, John F Woolley, Lekh Nath Dahal.
      Despite strong biological rationale for the use of type-I Interferons for the treatment of acute myeloid leukemia (AML), their usage is limited to few hematological malignancies. Here we propose that innate immune sensing machinery, particularly the Stimulator of Interferon Genes (STING) pathway may be exploited to deliver anti-leukemic effects in AML.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0871
  7. Semin Hematol. 2021 Jan;pii: S0037-1963(20)30076-7. [Epub ahead of print]58(1): 56-65
    The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia.
    Jesus D Gonzalez-Lugo, Samarpana Chakraborty, Amit Verma, Aditi Shastri.
      Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.
    DOI:  https://doi.org/10.1053/j.seminhematol.2020.12.003
  8. Hematology. 2021 Dec;26(1): 111-122
    Next-generation sequencing reveals gene mutations landscape and clonal evolution in patients with acute myeloid leukemia.
    Xiao Chen, Han Zhu, Chun Qiao, Sishu Zhao, Lu Liu, Yan Wang, Huimin Jin, Sixuan Qian, Yujie Wu.
       OBJECTIVES: The study aims to understand geneome diversification and complexity that developed in Acute myeloid leukemia (AML).
    METHODS: Next-generation sequencing (NGS) was used to identify the genetic profiles of 22 genes relevant to hematological malignancy in 204 patients with de novo non-M3 AML.
    RESULTS: At time of initial diagnosis, at least one mutation was identified in 80.9% of patients (165/204). The most commonly mutated gene was NPM1 (22.1%), followed by ASXL1 (18.1%), TET2 (18.1%), IDH2 (15.7%), CEBPA (14.7%), FLT3-ITD (13.2%) and DNMT3A (11.8%). Mutations landscape analysis indicated several patterns of co-occurring and mutual exclusive gene mutations. Some correlation was observed between gene mutations and clinicohematological features. Multivariate analysis showed that age >60 years, karyotypes, IDH2 and KIT mutations were the independent unfavorable prognostic factors for OS; NPM1-mut/ FLT3-ITD-wt was independently correlated with prolonged OS; whereas the independent poor risk factors for RFS were karyotypes, high WBC and RUNX1 mutation. According to different genotype demonstrated by multivariate analysis, 163 patients with intermediate-risk cytogenetics were classified into three subgroups: patients with NPM1-mut/ FLT3-ITD-wt or biallelic CEBPA mutation as favorable risk, patients with KIT, IDH2, TP53 or NRAS mutations as unfavorable risk, and the remaining was the intermediate risk. We also obtain information of clonal evolution during leukemia progression by observing five patients who underwent repeat NGS at relapse in our cohort.
    CONCLUSION: NGS techniques is a useful tool for discovering related gene mutations and clonal evolution in AML genomes, leading to novel targeted therapeutic approaches that could improve patients outcomes.
    Keywords:  Acute myeloid leukemia; clonal evolution; gene mutations; multivariate analysis; next-generation sequencing; prognostic factors; risk cytogenetics; targeted therapeutic approaches
    DOI:  https://doi.org/10.1080/16078454.2020.1858610
  9. Clin Cancer Res. 2021 Jan 25. pii: clincanres.4054.2020. [Epub ahead of print]
    Clinical responsiveness to All-trans Retinoic Acid is potentiated by LSD1 inhibition and associated with a quiescent transcriptome in myeloid malignancies.
    Mina Masoumeh Tayari, Helena Gomes Dos Santos, Deukwoo Kwon, Terrence Bradley, Amber Thomassen, Charles Jeng Chen, Yvonne Dinh, Aymee Perez, Artur Zelent, Lluis Morey, Luisa Cimmino, Ramin Shiekhattar, Ronan T Swords, Justin M Watts.
       PURPOSE: In preclinical studies, the LSD1 inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-APL acute myeloid leukemia (AML). We conducted a Phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).
    EXPERIMENTAL DESIGN: Seventeen patients were treated with ATRA and TCP (3 dose levels: 10 mg twice daily [BID], 20 mg BID, and 30 mg BID).
    RESULTS: ATRA-TCP had an acceptable safety profile. The maximum tolerated dose of TCP was 20 mg BID. Best responses included 1 morphologic leukemia-free state, 1 marrow complete remission with hematologic improvement, 2 stable disease with hematologic improvement, and 2 stable disease. By intention-to-treat, the overall response rate was 23.5% and clinical benefit rate 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared to non-responders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid (RA)-target genes in responders but not non-responders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.
    CONCLUSIONS: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of MDS and AML patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4054
  10. Leukemia. 2021 Jan 25.
    Late outcomes in survivors of childhood acute myeloid leukemia: a report from the St. Jude Lifetime Cohort Study.
    Neel S Bhatt, Malek J Baassiri, Wei Liu, Nickhill Bhakta, Wassim Chemaitilly, Matthew J Ehrhardt, Hiroto Inaba, Kevin Krull, Kirsten K Ness, Jeffrey E Rubnitz, Deokumar Srivastava, Leslie L Robison, Melissa M Hudson, Daniel A Mulrooney.
      Cumulative burden of chronic health conditions and neurocognitive and physical function were examined among survivors of childhood acute myeloid leukemia (AML) treated with hematopoietic cell transplant (HCT; n = 66) or conventional therapy (CT; n = 67). Survivors and controls underwent a comprehensive clinical assessment, and health conditions were graded using a modified version of the Common Terminology Criteria for Adverse Events. By age 40 years, HCT and CT survivors had an average 17.4 (95% confidence interval [CI] 14.6-20.1) and 9.3 (7.7-11.1) grade 1-4 conditions versus 3.8 (3.3-4.2) in community controls. Compared to controls, HCT survivors had a higher prevalence of hypertriglyceridemia (45.5% vs. 18.3%), hypercholesterolemia (47.0% vs. 30.9%), hypothyroidism (27.3% vs. 4.0%), and primary hypogonadism (p < 0.001). CT survivors had a higher prevalence of cardiomyopathy (11.9% vs. 2.7%) and hypertension (53.7% vs. 44.3%). Neurocognitive impairment was elevated across all domains compared to controls but did not differ by treatment modality. Compared to controls, a higher proportion of HCT survivors had impairments in strength and endurance; whereas flexibility and mobility impairments were noted among CT survivors. Despite successful advances in childhood AML therapy, many therapeutic exposures remain unchanged. These findings support ongoing investigations of novel therapies and strategies to ameliorate the risk of late morbidities.
    DOI:  https://doi.org/10.1038/s41375-021-01134-3
  11. Cancer Med. 2021 Jan 24.
    Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy.
    Min Ruan, Li-Peng Liu, Ao-Li Zhang, Ben Quan Qi, Fang Liu, Tian-Feng Liu, Xiao-Ming Liu, Xiao-Juan Chen, Wen-Yu Yang, Ye Guo, Li Zhang, Yao Zou, Yu-Mei Chen, Xiao-Fan Zhu.
       BACKGROUND: The preferred salvage treatment for children with relapsed/refractory acute myeloid leukemia (R/R-AML) remains unclear. The combination of cladribine/Ara-C/granulocyte-colony stimulating factor and mitoxantrone (CLAG-M) shown promising results in adult R/R-AML. We aim to investigate the efficacy and safety of CLAG-M versus mitoxantrone/etoposide/cytarabine (MEC) or idarubicin/etoposide/cytarabine (IEC) in R/R-AML children.
    METHODS: Fifty-five R/R-AML children were analyzed. The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) at 3-year were documented. Karyotype or mutations status were summarized as different risk groups.
    RESULTS: The ORR was achieved in 80% (16/20) and 51% (18/35) of patients after one-cycle of CLAG-M and MEC/IEC treatment (p < 0.001). The CLAG-M group's OS (66.8% ± 16.2% vs. 40.4% ± 10.9%, p = 0.019) and PFS (52.6% ± 13.7% vs. 34.9% ± 9.1%, p = 0.036) at 3-year was significantly higher than the MEC/IEC group. In high-risk patients, 33.3% experienced progression of disease (PD) and 22.2% dead in CLAG-M group, while 50% experienced PD and 43.8% dead in MEC/IEC. When it comes to low-risk group, none of them in CLAG-M experienced PD or death, while up to 50% of patients received MEC/IEC suffered PD, and all of them died eventually. Similar results were also found in the intermediate-risk group. Surprisingly, the presence of FLT3-ITD was associated with poor outcome in both groups. The most common adverse events were hematologic toxicities, and the incidence was similar in both group.
    CONCLUSIONS: CLAG-M group demonstrated effective palliation along with acceptable toxicity in R/R-AML patients. However, patients with FLT3-ITD may benefit less from CLAG-M, owing to higher PD rate and all-cause mortality than other patients.
    Keywords:  acute myeloid leukemia; children; cladribine; refractory; relapsed
    DOI:  https://doi.org/10.1002/cam4.3681
  12. FEBS J. 2021 Jan 29.
    The transcriptional regulation of normal and malignant blood cell development.
    Benjamin Edginton-White, Constanze Bonifer.
      Development of multicellular organisms requires the differential usage of our genetic information to change one cell fate into another. This process drives the appearance of different cell types that come together to form specialized tissues sustaining a healthy organism. In the last decade, by moving away from studying single genes towards a global view of gene expression control, a revolution has taken place in our understanding of how genes work together and how cells communicate to translate the information encoded in the genome into a body plan. The development of hematopoietic cells has long served as a paradigm of development in general. In this review, we highlight how transcription factors and chromatin components work together to shape the gene regulatory networks controlling gene expression in the hematopoietic system and to drive of blood cell differentiation. In addition, we outline how this process goes astray in blood cancers. We also touch upon emerging concepts that place these processes firmly into their associated subnuclear structures adding another layer of the control of differential gene expression.
    Keywords:  Hematopoiesis; acute myeloid leukemia; gene regulatory networks; nuclear compartments; transcription and chromatin
    DOI:  https://doi.org/10.1111/febs.15735
  13. Leuk Res. 2021 Jan 11. pii: S0145-2126(20)30197-1. [Epub ahead of print]101 106492
    Genetic characterization of acute myeloid leukemia patients with mutations in IDH1/2 genes.
    Pamela Acha, Montserrat Hoyos, Marta Pratcorona, Francisco Fuster-Tormo, Laura Palomo, Esther Ortega, Lurdes Zamora, Susana Vives, Isabel Granada, Julia Montoro, Antoni Garcia, Montserrat Arnan, Marta Cervera, Marta Canet, David Gallardo, Leonor Arenillas, Jordi Esteve, Joan Baragay, Olga Salamero, Cristina Motlló, Xavier Ortín, Jordi Sierra, Francesc Solé.
      
    DOI:  https://doi.org/10.1016/j.leukres.2020.106492
  14. Blood. 2021 Jan 19. pii: blood.2020009103. [Epub ahead of print]
    Modeling and targeting of erythroleukemia by hematopoietic genome editing.
    Ilaria Iacobucci, Chunxu Qu, Elena Varotto, Laura J Janke, Xu Yang, Aman Seth, Anang Shelat, Jake Friske, Reiji Fukano, Jiyang Yu, Burgess B Freeman, James A Kennedy, Adam S Sperling, Rena Zheng, Yingzhe Wang, Harini Jogiraju, Kirsten Dickerson, Debbie L Payne-Turner, Sarah M Morris, Emily Hollis, Nina J Ghosn, Georgia E Haggard, R Coleman Lindsley, Benjamin L Ebert, Charles G Mullighan.
      Acute erythroid leukemia (AEL) is characterized by distinct morphology, mutational spectrum, a lack of preclinical models and poor prognosis. Here, using multiplexed genome editing of mouse hematopoietic stem and progenitor cells and transplant assay, we developed preclinical models of AEL and non-erythroid acute leukemia and demonstrated the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1 and Nfix resulted in the development of leukemia with erythroid phenotype, and were accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational co-occurrence, with clones harboring a higher number of founder and secondary lesions (e.g. mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the PARP inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a mutant AEL and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has demonstrated the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors and therapeutic tractability in erythroid leukemogenesis.
    DOI:  https://doi.org/10.1182/blood.2020009103
  15. Blood. 2020 Dec 23. pii: blood.2019004509. [Epub ahead of print]
    Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis.
    Marcelo A Szymanski Toledo, Malrun Gatz, Stephanie Sontag, Karoline Veronika Gleixner, Gregor Eisenwort, Kristina Feldberg, Ahmed Emad Ibrahim Hamouda, Frederick Kluge, Riccardo Guareschi, Giulia Rossetti, Antonio Salvatore Sechi, Olli Dufva, Satu Mustjoki, Angela Maurer, Herdit M Schüler, Roman Goetzke, Till Braunschweig, Anne Kaiser, Jens Peter Panse, Mohamad Jawhar, Andreas Reiter, Frank Hilberg, Peter Ettmayer, Wolfgang Wagner, Steffen Koschmieder, Tim H Brümmendorf, Peter Valent, Nicolas Chatain, Martin Zenke.
      The KIT D816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. KIT D816V therefore represents a prime therapeutic target for SM. Here we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM (ASM) and mast cell leukemia (MCL) to develop a patient-specific SM disease model for mechanistic and drug discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, an FDA approved angiokinase inhibitor that targets VEGFR, PDGFR and FGFR, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the ATP binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V targeted therapy of advanced SM.
    DOI:  https://doi.org/10.1182/blood.2019004509
  16. Blood. 2021 Jan 28. 137(4): 569-572
    Acute myeloid leukemia measurable residual disease detection by flow cytometry in peripheral blood vs bone marrow.
    Colin D Godwin, Yi Zhou, Megan Othus, Mallette M Asmuth, Carole M Shaw, Kelda M Gardner, Brent L Wood, Roland B Walter, Elihu H Estey.
      
    DOI:  https://doi.org/10.1182/blood.2020006219
  17. Blood Adv. 2021 Jan 26. 5(2): 438-450
    DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes.
    Kensuke Kayamori, Yurie Nagai, Cheng Zhong, Satoshi Kaito, Daisuke Shinoda, Shuhei Koide, Wakako Kuribayashi, Motohiko Oshima, Yaeko Nakajima-Takagi, Masayuki Yamashita, Naoya Mimura, Hans Jiro Becker, Kiyoko Izawa, Satoshi Yamazaki, Satoshi Iwano, Atsushi Miyawaki, Ryoji Ito, Kaoru Tohyama, William Lennox, Josephine Sheedy, Marla Weetall, Emiko Sakaida, Koutaro Yokote, Atsushi Iwama.
      Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001461
  18. J Biol Chem. 2020 Apr 17. pii: S0021-9258(17)48565-6. [Epub ahead of print]295(16): 5496-5508
    Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function.
    Essam A Ghazaly, Farideh Miraki-Moud, Paul Smith, Chathunissa Gnanaranjan, Lola Koniali, Adedayo Oke, Marwa H Saied, Robert Petty, Janet Matthews, Randal Stronge, Simon P Joel, Bryan D Young, John Gribben, David C Taussig.
      Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.
    Keywords:  Acute myeloid leukemia; Sphingosine kinase (SphK); cell signaling; ceramide; chemotherapy; cytarabine; hypermethylation; leukemia; lipid metabolism; sphingolipid; sphingosine kinase interacting protein; sphingosine-1-phosphate (S1P)
    DOI:  https://doi.org/10.1074/jbc.RA119.010467
  19. Nat Commun. 2021 01 27. 12(1): 608
    Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1.
    Simon Renders, Arthur Flohr Svendsen, Jasper Panten, Nicolas Rama, Maria Maryanovich, Pia Sommerkamp, Luisa Ladel, Anna Rita Redavid, Benjamin Gibert, Seka Lazare, Benjamin Ducarouge, Katharina Schönberger, Andreas Narr, Manon Tourbez, Bertien Dethmers-Ausema, Erik Zwart, Agnes Hotz-Wagenblatt, Dachuan Zhang, Claudia Korn, Petra Zeisberger, Adriana Przybylla, Markus Sohn, Simon Mendez-Ferrer, Mathias Heikenwälder, Maik Brune, Daniel Klimmeck, Leonid Bystrykh, Paul S Frenette, Patrick Mehlen, Gerald de Haan, Nina Cabezas-Wallscheid, Andreas Trumpp.
      Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal.
    DOI:  https://doi.org/10.1038/s41467-020-20801-0
  20. Curr Opin Hematol. 2021 Jan 21.
    Therapeutic approaches targeting splicing factor mutations in myelodysplastic syndromes and acute myeloid leukemia.
    John W Figg, Juan M Barajas, Esther A Obeng.
       PURPOSE OF REVIEW: Mutations in components of the spliceosome are the most common acquired lesions in myelodysplastic syndromes (MDS) and are frequently identified in other myeloid malignancies with a high rate of progression to acute myeloid leukemia (AML) including chronic myelomonocytic leukemia and primary myelofibrosis. The only curative option for these disorders remains allogeneic stem-cell transplantation, which is associated with high morbidity and mortality in these patients. The purpose of this review is to highlight the recent therapeutic developments and strategies being pursued for clinical benefit in splicing factor mutant myeloid malignancies.
    RECENT FINDINGS: Cells harboring splicing factor mutations have increased aberrant splicing leading to R-loop formation and cell cycle stalling that create dependencies on Checkpoint kinase 1 (CHK1) activation and canonical splicing maintained by protein arginine methyltransferase activity. Both targeting of the spliceosome and targeting of the downstream consequences of splicing factor mutation expression show promise as selective strategies for the treatment of splicing factor-mutant myeloid malignancies.
    SUMMARY: An improved understanding of the therapeutic vulnerabilities in splicing factor-mutant MDS and AML has led to the development of clinical trials of small molecule inhibitors that target the spliceosome, ataxia telangectasia and Rad3 related (ATR)-CHK1 pathway, and methylation of splicing components.
    DOI:  https://doi.org/10.1097/MOH.0000000000000632
  21. Cancer Drug Resist. 2020 ;3 762-774
    PHGDH as a mechanism for resistance in metabolically-driven cancers.
    Richa Rathore, Charles R Schutt, Brian A Van Tine.
      At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells. The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments, which makes therapeutic exploitation complex but achievable. 3-phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers, including breast cancer, melanoma, and Ewing's sarcoma. This review will investigate the role of PHGDH in normal biological processes, leading to the role of PHGDH in the progression of cancer. With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth, we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.
    Keywords:  PHGDH; cancer; drug resistance; folate cycle; metabolism; one-carbon metabolism; serine
    DOI:  https://doi.org/10.20517/cdr.2020.46
  22. Blood. 2021 Jan 28. 137(4): 438-439
    Primum non nocere: allo-HSCT for AML in CR1.
    Roni Shouval, Robert J Soiffer.
      
    DOI:  https://doi.org/10.1182/blood.2020008641
  23. J Biol Chem. 2020 Mar 27. pii: S0021-9258(17)48748-5. [Epub ahead of print]295(13): 4212-4223
    Histone deacetylase 3 preferentially binds and collaborates with the transcription factor RUNX1 to repress AML1-ETO-dependent transcription in t(8;21) AML.
    Chun Guo, Jian Li, Nickolas Steinauer, Madeline Wong, Brent Wu, Alexandria Dickson, Markus Kalkum, Jinsong Zhang.
      In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1-eight-twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1-ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1-ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1-ETO and RUNX1 co-occupy the binding sites of AML1-ETO-activated genes. How this joined binding allows RUNX1 to antagonize AML1-ETO-mediated transcriptional activation is unclear. Here we show that RUNX1 functions as a bona fide repressor of transcription activated by AML1-ETO. Mechanistically, we show that RUNX1 is a component of the HDAC3 corepressor complex and that HDAC3 preferentially binds to RUNX1 rather than to AML1-ETO in t(8;21) AML cells. Studying the regulation of interleukin-8 (IL8), a newly identified AML1-ETO-activated gene, we demonstrate that RUNX1 and HDAC3 collaboratively repress AML1-ETO-dependent transcription, a finding further supported by results of genome-wide analyses of AML1-ETO-activated genes. These and other results from the genome-wide studies also have important implications for the mechanistic understanding of gene-specific coactivator and corepressor functions across the AML1-ETO/RUNX1 cistrome.
    Keywords:  AML1–ETO; GCN5; IL8/CXCL8; Runt-related transcription factor 1 (RUNX1); acetyltransferase; histone deacetylase 3 (HDAC3); interleukin; leukemia; p300; transcription coactivator; transcription corepressor; transcription factor
    DOI:  https://doi.org/10.1074/jbc.RA119.010707
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