bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021‒03‒14
twenty-one papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.
  2. Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.
  3. A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.
  4. Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles.
  5. Gene expression signature predicts relapse in adult patients with cytogenetically normal acute myeloid leukemia.
  6. A JAK/STAT-MEDIATED INFLAMMATORY SIGNALING CASCADE DRIVES ONCOGENESIS IN AF10-REARRANGED AML.
  7. Clinical Implications of Inflammation in Acute Myeloid Leukemia.
  8. The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia.
  9. Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.
  10. Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML.
  11. CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch.
  12. Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia.
  13. DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.
  14. Deregulated expression of circular RNAs in acute myeloid leukemia.
  15. Folate metabolism: a re-emerging therapeutic target in haematological cancers.
  16. The evolving concept of indications for allogeneic hematopoietic cell transplantation during first complete remission of acute myeloid leukemia.
  17. Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis.
  18. CSF3R T618I mutant chronic myelomonocytic leukemia (CMML) defines a proliferative CMML subtype enriched in ASXL1 mutations with adverse outcomes.
  19. A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.
  20. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial.
  21. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
  1. Blood Adv. 2021 Mar 09. 5(5): 1552-1564
    Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.
    Maximilian Stahl, Kamal Menghrajani, Andriy Derkach, Alexander Chan, Wenbin Xiao, Jacob Glass, Amber C King, Anthony F Daniyan, Christopher Famulare, Bernadette M Cuello, Troy Z Horvat, Omar Abdel-Wahab, Ross L Levine, Aaron D Viny, Eytan M Stein, Sheng F Cai, Mikhail Roshal, Martin S Tallman, Aaron D Goldberg.
      Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003734
  2. Blood Cancer Discov. 2021 Mar;2(2): 125-134
    Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.
    Ahmad S Alotaibi, Musa Yilmaz, Rashmi Kanagal-Shamanna, Sanam Loghavi, Tapan M Kadia, Courtney D DiNardo, Gautam Borthakur, Marina Konopleva, Sherry A Pierce, Sa A Wang, Guilin Tang, Veronica Guerra, Bachar Samra, Naveen Pemmaraju, Elias Jabbour, Nicholas J Short, Ghayas C Issa, Maro Ohanian, Guillermo Garcia-Manero, Kapil N Bhalla, Keyur P Patel, Koichi Takahashi, Michael Andreeff, Jorge E Cortes, Hagop M Kantarjian, Farhad Ravandi, Naval Daver.
      Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.
    Keywords:  FLT3 mutated AML; FLT3-inhibitor resistance; Type I; Type II; emergent mutations
    DOI:  https://doi.org/10.1158/2643-3230.bcd-20-0143
  3. Blood Cancer Discov. 2021 Mar;2(2): 146-161
    A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.
    Yihong Guan, Anand D Tiwari, James G Phillips, Metis Hasipek, Dale R Grabowski, Simona Pagliuca, Priyanka Gopal, Cassandra M Kerr, Vera Adema, Tomas Radivoyevitch, Yvonne Parker, Daniel J Lindner, Manja Meggendorfer, Mohamed Abazeed, Mikkeal A Sekeres, Omar Y Mian, Torsten Haferlach, Jaroslaw P Maciejewski, Babal K Jha.
      TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET-dioxygenase deficient cells. In addition, a TET-selective small molecule inhibitor decreased cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant, but not normal hematopoietic precursor cells in vitro and in vivo. While TET-inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells were, unlike mutations, reversible. Treatment with TET inhibitor suppressed the clonal evolution of TET2 mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2 mutant neoplasia.
    Keywords:  2-hydroxygluterate; 5hmC; IDH; MDS; TET2; α-ketoglutarate
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0173
  4. Exp Hematol. 2021 Mar 06. pii: S0301-472X(21)00095-3. [Epub ahead of print]
    Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles.
    Julie Mondet, Caroline Lo Presti, Simon Chevalier, Anne Bertrand, Sylvie Tondeur, Sandrine Blanchet, Anne Mc Leer, Karin Pernet-Gallay, Pascal Mossuz.
      Mitochondria are not only essential for cell metabolism and energy supply but they are also engaged in calcium homeostasis, reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondria disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very little data are available about the deregulation of their number and/or shape in leukemic cells, despite the evident link between ultrastructure and function. In this context, we analyzed the ultrastructural mitochondrial parameters (number per cell, mitochondria area, number of cristae/mitochondria, cristae thickness) in five leukemia cell lines (HEL, HL60, K562, KG1 and OCI-AML3) together with the functional assay of their respiratory profile. First of all, we show significant differences within basal respiration, maximal respiration, ATP production and spare respiratory capacity between our cell lines, confirming the various respiratory profiles between leukemia subtypes. Second, we highlight that these variations were obviously associated with significant inter-leukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1 characterized by the lowest number of mitochondria together with reduced cristae diameter displayed a very particularly deficient respiratory profile. In comparison, HEL and K562, both cell lines with high respiratory profiles, harbored the highest number of mitochondria/cells with high cristae diameters. Moreover, we show that K562, carrying ASXL1 mutation, presents significant mitochondria-endoplasmic reticulum (ER) deficiency by the decrease of the number of matrix granules, Mitochondria-associated Endoplasmic Reticulum membranes (MAMs) and Mitochondrial-derived vesicles (MDVs) precursors, which are implicated in the regulatory pathways of cell mortality via the process of mitophagy and of calcium homeostasis. On the opposite, HL60 carried high levels of matrix granules and MAMs together with a higher sensitivity to drug targeting mitochondria (Rotenone/Antimycine). We confirm the implication of ASXL1 mutation in this mitochondria dysregulation through the study of transcripts expression (from 415 patients coming from public data) involved in three mitochondria pathways i) the ER-mitochondria contacts (MAM), ii) matrix granules homeostasis, iii) MDVs precursors production. Altogether, our study offers new and original data on mitochondria structural alterations linked to deregulation of respiration profiles in AMLs and some genetic characteristics, suggesting that modifications of mitochondria shape and/or number in leukemic cells participate in chemoresistance and could be a targeted mechanism to regulate their proliferative potential.
    Keywords:  ASXL1 mutation; Mitochondria; endoplasmic reticulum stress; leukemia cell lines; matrix granules; mitochondria-associated endoplasmic reticulum membrane; mitochondrial respiration; mitochondrial-derived vesicles; transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.exphem.2021.03.001
  5. Blood Adv. 2021 Mar 09. 5(5): 1474-1482
    Gene expression signature predicts relapse in adult patients with cytogenetically normal acute myeloid leukemia.
    Christopher J Walker, Krzysztof Mrózek, Hatice Gulcin Ozer, Deedra Nicolet, Jessica Kohlschmidt, Dimitrios Papaioannou, Luke K Genutis, Marius Bill, Bayard L Powell, Geoffrey L Uy, Jonathan E Kolitz, Andrew J Carroll, Richard M Stone, Ramiro Garzon, John C Byrd, Ann-Kathrin Eisfeld, Albert de la Chapelle, Clara D Bloomfield.
      Although ∼80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), more than half of them relapse. Better identification of patients who are likely to relapse can help to inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML who were younger than 60 years of age and achieved a CR after induction treatment with standard "7+3" chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact outcome (ie, CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature that was strongly predictive of patient relapse (area under the receiver operating characteristics curve [AUC], 0.81). The signature consisted of 7 coding genes (GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55) and 3 long noncoding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P < .001), after adjustment for the FLT3-ITD, CEBPA, and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature's strong predictive value, with AUC = 0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients who are likely to relapse.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003727
  6. Blood. 2021 Mar 09. pii: blood.2020009023. [Epub ahead of print]
    A JAK/STAT-MEDIATED INFLAMMATORY SIGNALING CASCADE DRIVES ONCOGENESIS IN AF10-REARRANGED AML.
    Bo-Rui Chen, Anagha Deshpande, Karina Ofelia Barbosa, Maria Kleppe, Xue Lei, Narayana Yeddula, Pablo Sánchez Vela, Alexandre Rosa Campos, Robert J Wechsler-Reya, Anindya Bagchi, Soheil Meshinchi, Connie J Eaves, Irmela Jeremias, Torsten Haferlach, David A Frank, Ze'ev A Ronai, Sumit Chanda, Scott A Armstrong, Peter Adams, Ross L Levine, Aniruddha Deshpande.
      Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of AML driven by the most common AF10 fusion proteins, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent anti-oncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
    DOI:  https://doi.org/10.1182/blood.2020009023
  7. Front Oncol. 2021 ;11 623952
    Clinical Implications of Inflammation in Acute Myeloid Leukemia.
    Christian Récher.
      Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.
    Keywords:  FLT3; RUNX1; acute myeloid leukemia; chemoresistance; dexamethasone; glucocorticoids; inflammation; leukemic stem cells
    DOI:  https://doi.org/10.3389/fonc.2021.623952
  8. Front Immunol. 2020 ;11 627662
    The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia.
    Sarah Weber, Anastasia Parmon, Nina Kurrle, Frank Schnütgen, Hubert Serve.
      Myelodysplasticsyndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs. Here, we provide an overview of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML.
    Keywords:  acute myeloid leukemia; iron chelation; iron overload; microenvironment; myelodysplastic syndrome; reactive oxygen species
    DOI:  https://doi.org/10.3389/fimmu.2020.627662
  9. Blood. 2021 Mar 09. pii: blood.2020008729. [Epub ahead of print]
    Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.
    Margaux Sevin, Franck Debeurme, Lucie Laplane, Severine Badel, Margot Morabito, Hannah L Newman, Miguel Torres-Martin, Qin Yang, Bouchra Badaoui, Orianne Wagner-Ballon, Véronique Saada, Dorothée Selimoglu-Buet, Laurence Kraus-Berthier, Sébastien Banquet, Alix Derreal, Pierre Fenaux, Raphaël A Itzykson, Thorsten Braun, Gabriel Etienne, Celine Berthon, Sylvain Thepot, Oliver Kepp, Guido Kroemer, Eric Padron, Maria Eugenia Figueroa, Nathalie M Droin, Eric Solary.
      Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
    DOI:  https://doi.org/10.1182/blood.2020008729
  10. Sci Rep. 2021 Mar 12. 11(1): 5838
    Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML.
    Julia M Kempf, Sabrina Weser, Michael D Bartoschek, Klaus H Metzeler, Binje Vick, Tobias Herold, Kerstin Völse, Raphael Mattes, Manuela Scholz, Lucas E Wange, Moreno Festini, Enes Ugur, Maike Roas, Oliver Weigert, Sebastian Bultmann, Heinrich Leonhardt, Gunnar Schotta, Wolfgang Hiddemann, Irmela Jeremias, Karsten Spiekermann.
      Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
    DOI:  https://doi.org/10.1038/s41598-021-84708-6
  11. Leukemia. 2021 Mar 12.
    CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch.
    Xin He, Zijie Feng, Jian Ma, Xuyao Zhang, Sunbin Ling, Yan Cao, Bowen Xing, Yuan Wu, Lei Wang, Bryson W Katona, Carl H June, Xianxin Hua.
      
    DOI:  https://doi.org/10.1038/s41375-021-01208-2
  12. Nat Commun. 2021 03 11. 12(1): 1583
    Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia.
    Benjamin Demaree, Cyrille L Delley, Harish N Vasudevan, Cheryl A C Peretz, David Ruff, Catherine C Smith, Adam R Abate.
      Studies of acute myeloid leukemia rely on DNA sequencing and immunophenotyping by flow cytometry as primary tools for disease characterization. However, leukemia tumor heterogeneity complicates integration of DNA variants and immunophenotypes from separate measurements. Here we introduce DAb-seq, a technology for simultaneous capture of DNA genotype and cell surface phenotype from single cells at high throughput, enabling direct profiling of proteogenomic states in tens of thousands of cells. To demonstrate the approach, we analyze the disease of three patients with leukemia over multiple treatment timepoints and disease recurrences. We observe complex genotype-phenotype dynamics that illustrate the subtlety of the disease process and the degree of incongruity between blast cell genotype and phenotype in different clinical scenarios. Our results highlight the importance of combined single-cell DNA and protein measurements to fully characterize the heterogeneity of leukemia.
    DOI:  https://doi.org/10.1038/s41467-021-21810-3
  13. Genome Res. 2021 Mar 11. pii: gr.269233.120. [Epub ahead of print]
    DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.
    Brian Giacopelli, Min Wang, Ada Cleary, Yue-Zhong Wu, Anna Reister Schultz, Maximilian Schmutz, James S Blachly, Ann-Kathrin Eisfeld, Bethany Mundy-Bosse, Sebastian Vosberg, Philipp A Greif, Rainer Claus, Lars Bullinger, Ramiro Garzon, Kevin R Coombes, Clara D Bloomfield, Brian J Druker, Jeffrey W Tyner, John C Byrd, Christopher C Oakes.
      Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved sub-classification and understanding of the biology of the disease. Here we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed 'epitypes') using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes demonstrated developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem cell-like methylation features showed inferior overall survival along with upregulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem cell-like methylation patterns. These results demonstrate that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
    DOI:  https://doi.org/10.1101/gr.269233.120
  14. Blood Adv. 2021 Mar 09. 5(5): 1490-1503
    Deregulated expression of circular RNAs in acute myeloid leukemia.
    Susanne Lux, Tamara J Blätte, Bernhard Gillissen, Antje Richter, Sibylle Cocciardi, Sabrina Skambraks, Klaus Schwarz, Hubert Schrezenmeier, Hartmut Döhner, Konstanze Döhner, Anna Dolnik, Lars Bullinger.
      Circular RNAs (circRNAs) are dynamically regulated during differentiation and show cell type-specific expression, which is altered in cancer and can have a direct impact on its various hallmarks. We hypothesized that circRNA expression is deregulated in acute myeloid leukemia (AML) and that circRNA candidates might contribute to the pathogenesis of the disease. To identify leukemia-associated and differentiation-independent changes in circRNA expression, we determined the circular RNAome of 61 AML patients and 16 healthy hematopoietic stem and progenitor cell (HSPC) samples using ribosomal RNA-depleted RNA sequencing. We found hundreds of circRNAs that were differentially expressed between AML and healthy HSPCs. Gene set analysis found that many of these circRNAs were transcribed from genes implicated in leukemia biology. We discovered a circRNA derived from the T-cell transcription factor gene B cell CLL/lymphoma 11B, circBCL11B, which was exclusively expressed in AML patients, but not detected in healthy HSPCs, and associated with a T-cell-like gene expression signature. We were able to validate this finding in an independent cohort of 332 AML patients. Knockdown of circBCL11B had a negative effect on leukemic cell proliferation and resulted in increased cell death of leukemic cells, thereby suggesting circBCL11B as a novel functionally relevant candidate in AML pathogenesis. In summary, our study enables comprehensive insights into circRNA expression changes upon leukemic transformation and provides valuable information on the biology of leukemic cells and potential novel pathway dependencies that are relevant for AML therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003230
  15. Leukemia. 2021 Mar 11.
    Folate metabolism: a re-emerging therapeutic target in haematological cancers.
    Martha M Zarou, Alexei Vazquez, G Vignir Helgason.
      Folate-mediated one carbon (1C) metabolism supports a series of processes that are essential for the cell. Through a number of interlinked reactions happening in the cytosol and mitochondria of the cell, folate metabolism contributes to de novo purine and thymidylate synthesis, to the methionine cycle and redox defence. Targeting the folate metabolism gave rise to modern chemotherapy, through the introduction of antifolates to treat paediatric leukaemia. Since then, antifolates, such as methotrexate and pralatrexate have been used to treat a series of blood cancers in clinic. However, traditional antifolates have many deleterious side effects in normal proliferating tissue, highlighting the urgent need for novel strategies to more selectively target 1C metabolism. Notably, mitochondrial 1C enzymes have been shown to be significantly upregulated in various cancers, making them attractive targets for the development of new chemotherapeutic agents. In this article, we present a detailed overview of folate-mediated 1C metabolism, its importance on cellular level and discuss how targeting folate metabolism has been exploited in blood cancers. Additionally, we explore possible therapeutic strategies that could overcome the limitations of traditional antifolates.
    DOI:  https://doi.org/10.1038/s41375-021-01189-2
  16. Bone Marrow Transplant. 2021 Mar 08.
    The evolving concept of indications for allogeneic hematopoietic cell transplantation during first complete remission of acute myeloid leukemia.
    Masamitsu Yanada.
      The long-standing debate of whether patients with acute myeloid leukemia (AML) should proceed to allogeneic hematopoietic cell transplantation (HCT) during first complete remission (CR1) remains unsettled. Although allogeneic HCT during CR1 used to be recommended for those with intermediate or poor cytogenetics if they had a matched sibling donor, the concept of indications for allogeneic HCT during CR1 has been evolving by virtue of advances in understanding of the molecular pathogenesis of AML and innovations in transplantation practice attained over the last few decades. The incorporation of molecular profiles of leukemia has been shown to contribute to further refinements of risk classification that had previously relied mostly on cytogenetics, while the progress in transplantation procedures has made it possible to perform transplantations more safely even for patients without a matched sibling donor. These significant changes have underpinned the need to reappraise indications for allogeneic HCT during CR1 of AML. Improvements in clinical applications of genetic and measurable residual disease information as well as in transplantation technology are expected to further refine indications for allogeneic HCT during CR1, and thus promote an individualized approach for the treatment of AML.
    DOI:  https://doi.org/10.1038/s41409-021-01247-4
  17. Blood Adv. 2021 Mar 09. 5(5): 1540-1551
    Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis.
    Florian Renosi, Anne Roggy, Ambre Giguelay, Lou Soret, Pierre-Julien Viailly, Meyling Cheok, Sabeha Biichle, Fanny Angelot-Delettre, Vahid Asnafi, Elizabeth Macintyre, Sandrine Geffroy, Mary Callanan, Tony Petrella, Eric Deconinck, Etienne Daguindau, Véronique Harrivel, Sabrina Bouyer, Véronique Salaun, Pascale Saussoy, Jean Feuillard, Pascal Fuseau, Philippe Saas, Olivier Adotévi, Fabrice Jardin, Christophe Ferrand, Claude Preudhomme, Jacques Colinge, Christophe Roumier, Francine Garnache-Ottou.
      Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3- CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003359
  18. Blood Cancer J. 2021 Mar 11. 11(3): 54
    CSF3R T618I mutant chronic myelomonocytic leukemia (CMML) defines a proliferative CMML subtype enriched in ASXL1 mutations with adverse outcomes.
    Evandro D Bezerra, Terra L Lasho, Christy M Finke, Antoine N Saliba, Michelle A Elliott, Animesh D Pardanani, Naseema Gangat, Abhishek A Mangaonkar, Rhett P Ketterling, Ayalew Tefferi, Eric Solary, Mrinal M Patnaik.
      
    DOI:  https://doi.org/10.1038/s41408-021-00449-9
  19. Leuk Res. 2021 Mar 02. pii: S0145-2126(21)00056-4. [Epub ahead of print]104 106555
    A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.
    Jacqueline S Garcia, Ronan T Swords, Gail J Roboz, Meagan A Jacoby, Guillermo Garcia-Manero, Wan-Jen Hong, Xiaoqing Yang, Ying Zhou, Uwe Platzbecker, David P Steensma, Johannes E Wolff, Pierre Fenaux.
      The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.
    Keywords:  Azacitidine; Higher-Risk; Hypomethylating agent; Myelodysplastic syndromes; Overall survival
    DOI:  https://doi.org/10.1016/j.leukres.2021.106555
  20. Leukemia. 2021 Mar 11.
    Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial.
    Jerald P Radich, Andreas Hochhaus, Tamás Masszi, Andrzej Hellmann, Jesper Stentoft, María Teresa Gómez Casares, J Valentín García-Gutiérrez, Eibhlin Conneally, Philipp D le Coutre, Norbert Gattermann, Bruno Martino, Susanne Saussele, Francis J Giles, David M Ross, Paola Aimone, Sai Li, Ksenia Titorenko, Giuseppe Saglio.
      The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR4.5. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. The Kaplan-Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.
    DOI:  https://doi.org/10.1038/s41375-021-01205-5
  21. N Engl J Med. 2021 Mar 11. 384(10): 924-935
    Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
    Eric J Duncavage, Molly C Schroeder, Michele O'Laughlin, Roxanne Wilson, Sandra MacMillan, Andrew Bohannon, Scott Kruchowski, John Garza, Feiyu Du, Andrew E O Hughes, Josh Robinson, Emma Hughes, Sharon E Heath, Jack D Baty, Julie Neidich, Matthew J Christopher, Meagan A Jacoby, Geoffrey L Uy, Robert S Fulton, Christopher A Miller, Jacqueline E Payton, Daniel C Link, Matthew J Walter, Peter Westervelt, John F DiPersio, Timothy J Ley, David H Spencer.
      BACKGROUND: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated.METHODS: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing.
    RESULTS: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different.
    CONCLUSIONS: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2024534
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