bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021‒11‒28
twenty-one papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML).
  2. Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches.
  3. The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics.
  4. Hematopoiesis under telomere attrition at the single-cell resolution.
  5. Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance.
  6. Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia.
  7. A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia.
  8. Immune composition and its association with hematologic recovery after chemotherapeutic injury in acute myeloid leukemia.
  9. FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.
  10. Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis.
  11. An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy.
  12. Asciminib for CML: same target, new arrow.
  13. Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia.
  14. CD34 + CD38-CLL1+ leukemic stem cells persistence measured by multiparametric flow cytometry is a biomarker of poor prognosis in adult patients with acute myeloid leukemia.
  15. Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in Adult T-cell leukemia/lymphoma.
  16. GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized double blinded phase 2 trial.
  17. A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.
  18. Mechanism for the activation of the anaplastic lymphoma kinase receptor.
  19. Treatment Failure in Acute Myeloid Leukemia: Focus on the Role of Extracellular Vesicles.
  20. Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial.
  21. Structural basis for ligand reception by anaplastic lymphoma kinase.
  1. Biomedicines. 2021 Nov 17. pii: 1704. [Epub ahead of print]9(11):
    Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML).
    Hanane Djamai, Jeannig Berrou, Mélanie Dupont, Marie-Magdelaine Coudé, Marc Delord, Emmanuelle Clappier, Alice Marceau-Renaut, Anna Kaci, Emmanuel Raffoux, Raphaël Itzykson, Caroline Berthier, Hsin-Chieh Wu, Rita Hleihel, Ali Bazarbachi, Hugues de Thé, André Baruchel, Claude Gardin, Hervé Dombret, Thorsten Braun.
      BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.
    Keywords:  AML; ATO; ATRA; BET inhibitors; HOX genes; JQ1; NPM1; OTX015 (MK-8628); differentiation
    DOI:  https://doi.org/10.3390/biomedicines9111704
  2. Leuk Lymphoma. 2021 Nov 25. 1-10
    Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches.
    Amanda C Przespolewski, Scott Portwood, Eunice S Wang.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-β. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased in vivo disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.
    Keywords:  AML; Immunotherapy; PD-1; checkpoint inhibitor; innate immune agonist
    DOI:  https://doi.org/10.1080/10428194.2021.1992614
  3. iScience. 2021 Nov 19. 24(11): 103350
    The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics.
    Elena Porcù, Maddalena Benetton, Valeria Bisio, Ambra Da Ros, Claudia Tregnago, Giulia Borella, Carlo Zanon, Matteo Bordi, Giuseppe Germano, Sabrina Manni, Silvia Campello, Dinesh S Rao, Franco Locatelli, Martina Pigazzi.
      Patients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNA CDK6-AS1 able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. CDK6-AS1 silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued. This latter phenomenon derived from RUNX1 transcriptional control, responsible for the stemness of hematopoietic precursors and for the block of differentiation in AML. By CDK6-AS1 silencing in vitro, AML mitochondrial mass decreased with augmented pharmacological sensitivity to mitochondria-targeting drugs. In vivo, the combination of tigecycline and cytarabine reduced leukemia progression in the AML-PDX model with high CDK6-AS1 levels, supporting the concept of a mitochondrial vulnerability. Together, these findings uncover CDK6-AS1 as crucial in myeloid differentiation and mitochondrial mass regulation.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103350
  4. Nat Commun. 2021 Nov 25. 12(1): 6850
    Hematopoiesis under telomere attrition at the single-cell resolution.
    Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A Class, Kelly A Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A Bertuch, Courtney D DiNardo, Guillermo Garcia-Manero, Neal S Young, Karen Dwyer, Simona Colla.
      The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
    DOI:  https://doi.org/10.1038/s41467-021-27206-7
  5. Cells. 2021 Nov 03. pii: 2992. [Epub ahead of print]10(11):
    Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance.
    Maximilian Fleischmann, Mike Fischer, Ulf Schnetzke, Colin Fortner, Joanna Kirkpatrick, Florian H Heidel, Andreas Hochhaus, Sebastian Scholl.
      OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization.AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA.
    METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography-tandem mass spectrometry was performed to assess differential protein expression.
    RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment.
    CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies.
    Keywords:  17-AAG; AML; FLT3-ITD; HSP90; TKI; VPA; rapamycin; resistance; tunicamycin
    DOI:  https://doi.org/10.3390/cells10112992
  6. Nat Commun. 2021 Nov 26. 12(1): 6936
    Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia.
    Limei Wu, Srinivas Chatla, Qiqi Lin, Fabliha Ahmed Chowdhury, Werner Geldenhuys, Wei Du.
      Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.
    DOI:  https://doi.org/10.1038/s41467-021-27300-w
  7. Cells. 2021 Oct 21. pii: 2833. [Epub ahead of print]10(11):
    A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia.
    Seyed Mohammadreza Bolandi, Mahdi Pakjoo, Peyman Beigi, Mohammad Kiani, Ali Allahgholipour, Negar Goudarzi, Jamshid S Khorashad, Anna M Eiring.
      Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
    Keywords:  acute myeloid leukemia; bone marrow microenvironment; drug resistance; leukemic stem cell
    DOI:  https://doi.org/10.3390/cells10112833
  8. Exp Hematol. 2021 Nov 17. pii: S0301-472X(21)00426-4. [Epub ahead of print]
    Immune composition and its association with hematologic recovery after chemotherapeutic injury in acute myeloid leukemia.
    Keane Jared Guillaume Kenswil, Paola Pisterzi, Jacqueline Feyen, Mariëtte Ter Borg, Elwin Rombouts, Eric Braakman, Marc Hermanus Gerardus Petrus Raaijmakers.
      Chemotherapy-induced bone marrow (BM) injury is a significant cause of morbidity and mortality in acute myeloid leukemia (AML). Time to hematologic recovery after standard ('7+3') myeloablative chemotherapy can vary considerably between patients, but the factors that drive or predict BM recovery remain incompletely understood. Here, we assessed the composition of innate and adaptive immune subsets in the regenerating BM (day 17) after induction chemotherapy and related it to hematologic recovery in AML. T cells, and in particular the CD4 central memory (CD4CM) T cell subset, were significantly enriched in the BM after chemotherapy, suggesting relative chemo-resistance of cells providing long-term memory for systemic pathogens. In contrast, B cells and other hematopoietic subsets were depleted. Higher frequencies of the CD4CM T cell subset were associated with delayed hematopoietic recovery, while a high frequency of NK cells related to faster recovery of neutrophil counts. The NK/CD4CM ratio in the BM after chemotherapy was significantly associated with the time to subsequent neutrophil recovery (Spearman's ρ = -0.723, p < 0.001, FDR < 0.01). The data provide novel insights into adaptive immune cell recovery after injury and identify the NK/CD4CM index as a putative predictor of hematopoietic recovery in AML.
    Keywords:  Chemotherapy; bone marrow; chemotherapy-induced myelosuppression; hematologic recovery; immunosuppression; neutropenia; niche; regeneration
    DOI:  https://doi.org/10.1016/j.exphem.2021.11.003
  9. Sci Rep. 2021 Nov 22. 11(1): 22678
    FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.
    Kouhei Yamawaki, Isamu Shiina, Takatsugu Murata, Satoru Tateyama, Yutarou Maekawa, Mariko Niwa, Motoyuki Shimonaka, Koji Okamoto, Toshihiro Suzuki, Toshirou Nishida, Ryo Abe, Yuuki Obata.
      FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30-40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.
    DOI:  https://doi.org/10.1038/s41598-021-02221-2
  10. Cancers (Basel). 2021 Nov 12. pii: 5677. [Epub ahead of print]13(22):
    Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis.
    Miriam Saiz-Rodríguez, Jorge Labrador, Beatriz Cuevas, David Martínez-Cuadrón, Verónica Campuzano, Raquel Alcaraz, Isabel Cano, Miguel A Sanz, Pau Montesinos.
      Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule of each drug in AML. A systematic review and meta-analysis on the efficacy of decitabine and azacitidine monotherapy in newly diagnosed AML was conducted. Randomised controlled trials and retrospective studies were included. A total of 2743 patients from 23 cohorts were analysed (10 cohorts of azacitidine and 13 of decitabine). Similar response rates were observed for azacitidine (38%, 95% CI: 30-47%) compared to decitabine (40%, 95% CI: 32-48%) (p = 0.825). Overall survival (OS) between azacitidine (10.04 months, 95% CI: 8.36-11.72) and decitabine (8.79 months, 95% CI: 7.62-9.96) was also similar (p = 0.386). Patients treated with azacitidine showed a lower median OS when azacitidine was administered for 5 days (6.28 months, 95% CI: 4.23-8.32) compared to the standard 7-day schedule (10.83 months, 95% CI: 9.07-12.59, p = 0.002). Among patients treated with decitabine, response rates and OS were not significantly different between 5-day and 10-day decitabine regimens. Despite heterogeneity between studies, we found no differences in response rates and OS in AML patients treated with azacitidine or decitabine.
    Keywords:  acute myeloid leukaemia; azacitidine; decitabine; elderly; meta-analysis
    DOI:  https://doi.org/10.3390/cancers13225677
  11. J Exp Med. 2022 Jan 03. pii: e20210836. [Epub ahead of print]219(1):
    An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy.
    Bassem D Khalil, Roberto Sanchez, Tasrina Rahman, Carolina Rodriguez-Tirado, Stefan Moritsch, Alba Rodriguez Martinez, Brett Miles, Eduardo Farias, Mihaly Mezei, Ana Rita Nobre, Deepak Singh, Nupura Kale, Karl Christoph Sproll, Maria Soledad Sosa, Julio A Aguirre-Ghiso.
      We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.
    DOI:  https://doi.org/10.1084/jem.20210836
  12. Blood. 2021 Nov 25. 138(21): 2009-2010
    Asciminib for CML: same target, new arrow.
    Charles A Schiffer.
      
    DOI:  https://doi.org/10.1182/blood.2021013257
  13. Am J Blood Res. 2021 ;11(5): 472-497
    Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia.
    Harsh Goel, Ekta Rahul, Ishan Gupta, Anita Chopra, Amar Ranjan, Aditya Kumar Gupta, Jagdish Prasad Meena, Ganesh Kumar Viswanathan, Sameer Bakhshi, Aroonima Misra, Showket Hussain, Ritesh Kumar, Archana Singh, G K Rath, Ashok Sharma, Sandeep Mittan, Pranay Tanwar.
      Acute myeloid leukemia (AML) is a complex, aggressive myeloid neoplasm characterized by frequent somatic mutations that influence different functional categories' genes, resulting in maturational arrest and clonal expansion. AML can arise de novo (dn-AML) or can be secondary AML (s-AML) refers to a leukemic process which may arise from an antecedent hematologic disorder (AHD-AML), mostly from a myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or can be the result of an antecedent cytotoxic chemotherapy or radiation therapy (therapy-related AML, t-AML). Clinical and biological features in secondary and therapy-related AML are distinct from de novo AML. Secondary and therapy-related AML occurs mainly in the elderly population and responds worse to therapy with higher relapse rates due to resistance to cytotoxic chemotherapy. Over the last decade, advances in molecular genetics have disclosed the sub-clonal architecture of secondary and therapy-related AML. Recent investigations have revealed that cytogenetic abnormalities and underlying genetic aberrations (mutations) are likely to be significant factors dictating prognosis and critical impacts on treatment outcome. Secondary and therapy-related AML have a poorer outcome with adverse cytogenetic abnormalities and higher recurrences of unfavorable mutations compared to de novo AML. In this review, we present an overview of the clinical features of secondary and therapy-related AML and address the function of genetic mutations implicated in the pathogenesis of secondary leukemia. Detailed knowledge of the pathogenetic mechanisms gives an overview of new prognostic markers, including targetable mutations that will presumably lead to the designing and developing novel molecular targeted therapies for secondary and therapy-related AML. Despite significant advances in knowing the genetic aspect of secondary and therapy-related AML, its influence on the disease's pathophysiology, standard treatment prospects have not significantly evolved during the past three decades. Thus, we conclude this review by summarizing the modern and developing treatment strategies in secondary and therapy-related acute myeloid leukemia.
    Keywords:  Secondary AML; leukemia; therapy related AML
  14. Leuk Lymphoma. 2021 Nov 21. 1-5
    CD34 + CD38-CLL1+ leukemic stem cells persistence measured by multiparametric flow cytometry is a biomarker of poor prognosis in adult patients with acute myeloid leukemia.
    Raffaele Palmieri, Francesco Buccisano, Valentina Arena, Maria Antonietta Irno Consalvo, Alfonso Piciocchi, Luca Maurillo, Maria Ilaria DelPrincipe, Ambra Di Veroli, Giovangiacinto Paterno, Consuelo Conti, Daniela Fraboni, Maria Teresa Voso, William Arcese, Adriano Venditti.
      
    DOI:  https://doi.org/10.1080/10428194.2021.2005042
  15. Blood. 2021 Nov 24. pii: blood.2021012734. [Epub ahead of print]
    Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in Adult T-cell leukemia/lymphoma.
    Takashi Ishio, Sarvesh Kumar, Joji Shimono, Anusara Daenthanasanmak, Sigrid Dubois, Yuquan Lin, Bonita R Bryant, Michael N Petrus, Emmanuel Bachy, Da Wei Huang, Yandan Yang, Patrick L Green, Hiroo Hasegawa, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takashi Yokota, Kanako C Hatanaka, Yutaka Hatanaka, Shinya Tanaka, Yoshihiro Matsuno, Yibin Yang, Satoshi Hashino, Takanori Teshima, Thomas A Waldmann, Louis M Staudt, Masao Nakagawa.
      Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
    DOI:  https://doi.org/10.1182/blood.2021012734
  16. Blood Adv. 2021 Nov 22. pii: bloodadvances.2021006255. [Epub ahead of print]
    GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized double blinded phase 2 trial.
    Vincent T Ho, Haesook T Kim, Jennifer Brock, Ilene Galinsky, Heather Daley, Carol G Reynolds, Augustine Weber, Olga Pozdnyakova, Mariano Severgnini, Sarah Nikiforow, Corey S Cutler, John Koreth, Edwin P Alyea, Joseph H Antin, Mahasweta Gooptu, Rizwan Romee, Roman M Shapiro, Yi-Bin Chen, Jacalyn Rosenblatt, David Avigan, F Stephen Hodi, Glenn Dranoff, Catherine J Wu, Jerome Ritz, Robert J Soiffer.
      Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete GM-CSF (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase II trial of GVAX after HSCT for MDS-EB or relapsed/refractory AML. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs. placebo (1:1) was stratified by disease, transplant center, and conditioning. GVHD prophylaxis included tacrolimus and methotrexate. GVAX or placebo started between day +30-45 if there was engraftment and no GVHD. Vaccines were administered SC/ID weekly x 3, then q2 wks x 3. Tacrolimus taper began after vaccine completion. 123 patients enrolled, 92 proceeded to HSCT, and 57 (GVAX 30, Placebo 27) received at least 1 vaccination. No CTC grade ≥ 3 vaccine related adverse events were reported, but injection site reactions were more common after GVAX (10 vs. 1, p=0.006). With a median follow up of 39 months (range, 9-89), 18-month PFS, OS and relapse incidence were 53% vs 55% (p=0.79), 63% vs. 59% (p= 0.86), and 30% vs. 37% (p=0.51) for GVAX and placebo, respectively. NRM at 18 months was 17% vs. 7.7% (p=0.18), Grade II-IV aGVHD at 12 months 34% vs. 12% (p=0.13), and cGVHD at 3 years 49% vs. 57% for GVAX and placebo, respectively, p=0.26. Reconstitution of T, B, and NK cells were not decreased or enhanced by GVAX. There were no differences in serum MICA/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for MDS/AML. (Clinicaltrials.gov identifier: NCT01773395).
    DOI:  https://doi.org/10.1182/bloodadvances.2021006255
  17. Nat Commun. 2021 Nov 25. 12(1): 6905
    A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.
    Siobhan Rice, Thomas Jackson, Nicholas T Crump, Nicholas Fordham, Natalina Elliott, Sorcha O'Byrne, Maria Del Mar Lara Fanego, Dilys Addy, Trisevgeni Crabb, Carryl Dryden, Sarah Inglott, Dariusz Ladon, Gary Wright, Jack Bartram, Philip Ancliff, Adam J Mead, Christina Halsey, Irene Roberts, Thomas A Milne, Anindita Roy.
      Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.
    DOI:  https://doi.org/10.1038/s41467-021-27270-z
  18. Nature. 2021 Nov 24.
    Mechanism for the activation of the anaplastic lymphoma kinase receptor.
    Andrey V Reshetnyak, Paolo Rossi, Alexander G Myasnikov, Munia Sowaileh, Jyotidarsini Mohanty, Amanda Nourse, Darcie J Miller, Irit Lax, Joseph Schlessinger, Charalampos G Kalodimos.
      Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system1,2. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies3. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma4-7. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain8,9. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands10-14 to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
    DOI:  https://doi.org/10.1038/s41586-021-04140-8
  19. Leuk Res. 2021 Nov 16. pii: S0145-2126(21)01752-5. [Epub ahead of print]112 106751
    Treatment Failure in Acute Myeloid Leukemia: Focus on the Role of Extracellular Vesicles.
    Reza Mirfakhraie, Leila Noorazar, Mozhdeh Mohammadian, Abbas Hajifathali, Majid Gholizadeh, Maryam Salimi, Ghazaleh Sankanian, Elham Roshandel, Mahshid Mehdizadeh.
      Acute myeloblastic leukemia (AML) is one of the most common types of blood malignancies that results in an AML-associated high mortality rate each year. Several causes have been reported as prognostic factors for AML in children and adults, the most important of which are cytogenetic abnormalities and environmental risk factors. Following the discovery of numerous drugs for AML treatment, leukemic cells sought a way to escape from the cytotoxic effects of chemotherapy drugs, leading to treatment failure. Nowadays, comprehensive studies have looked at the role of extracellular vesicles (EVs) secreted by AML blasts and how the microenvironment of the tumor changes in favor of cancer progression and survival to discover the mechanisms of treatment failure to choose the well-advised treatment. Reports show that malignant cells secrete EVs that transmit messages to adjacent cells and the tumor's microenvironment. By secreting EVs, containing immune-inhibiting cytokines, AML cells inactivate the immune system against malignant cells, thus ensuring their survival. Also, increased secretion of EVs in various malignancies indicates an unfavorable prognostic factor and the possibility of drug resistance. In this study, we briefly reviewed the challenges of treating AML with a glance at the EVs' role in this process. It is hoped that with a deeper understanding of EVs, new therapies will be developed to eliminate the relapse of leukemic cells.
    Keywords:  Acute myeloblastic leukemia; Drug resistance; Exosome; Extracellular vesicle; Microvesicle; Treatment failure
    DOI:  https://doi.org/10.1016/j.leukres.2021.106751
  20. Lancet Haematol. 2021 Dec;pii: S2352-3026(21)00333-1. [Epub ahead of print]8(12): e902-e911
    Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial.
    Kazunori Murai, Hiroshi Ureshino, Takashi Kumagai, Hideo Tanaka, Kaichi Nishiwaki, Satoshi Wakita, Koiti Inokuchi, Toshihiro Fukushima, Chikashi Yoshida, Nobuhiko Uoshima, Toru Kiguchi, Masayuki Mita, Jun Aoki, Satoshi Kimura, Kaori Karimata, Kensuke Usuki, Joji Shimono, Yoshiaki Chinen, Junya Kuroda, Yasufumi Matsuda, Kensuke Nakao, Takaaki Ono, Katsumichi Fujimaki, Hirohiko Shibayama, Chisaki Mizumoto, Tomoharu Takeoka, Katsuhiro Io, Takeshi Kondo, Masatomo Miura, Yousuke Minami, Takayuki Ikezoe, Jun Imagawa, Ayako Takamori, Atsushi Kawaguchi, Junichi Sakamoto, Shinya Kimura.
      BACKGROUND: BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase.METHODS: DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period.
    FINDINGS: Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed.
    INTERPRETATION: Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population.
    FUNDING: Bristol-Myers Squibb.
    DOI:  https://doi.org/10.1016/S2352-3026(21)00333-1
  21. Nature. 2021 Nov 24.
    Structural basis for ligand reception by anaplastic lymphoma kinase.
    Tongqing Li, Steven E Stayrook, Yuko Tsutsui, Jianan Zhang, Yueyue Wang, Hengyi Li, Andrew Proffitt, Stefan G Krimmer, Mansoor Ahmed, Olivia Belliveau, Ian X Walker, Krishna C Mudumbi, Yoshihisa Suzuki, Irit Lax, Diego Alvarado, Mark A Lemmon, Joseph Schlessinger, Daryl E Klein.
      The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.
    DOI:  https://doi.org/10.1038/s41586-021-04141-7
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