bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒07‒26
eighteen papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1.
  2. PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells.
  3. Targeting the MAPK/ERK and PI3K/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia Cells.
  4. Targeting the alpha subunit of IL-3 receptor (CD123) in patients with acute leukemia.
  5. Cell Growth Inhibition of Saponin XII from Dipsacus japonicus Miq. on Acute Myeloid Leukemia Cells.
  6. Signalling input from divergent pathways subverts B cell transformation.
  7. Genetic and Molecular Basis of Heterogeneous NK Cell Responses against Acute Leukemia.
  8. Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.
  9. Prognostic value of monocyte subset distribution in chronic myelomonocytic leukemia: results of a multicenter study.
  10. Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML.
  11. Identifying strategies to target the metabolic flexibility of tumours.
  12. Potential targeting of FLT3 AML.
  13. Proteome activity landscapes of tumor cell lines determine drug responses.
  14. DDX5-targeting fully human monoclonal autoantibody inhibits proliferation and promotes differentiation of acute promyelocytic leukemia cells by increasing ROS production.
  15. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy.
  16. PPM1D Knockdown Suppresses Cell Proliferation, Promotes Cell Apoptosis, and Activates p38 MAPK/p53 Signaling Pathway in Acute Myeloid Leukemia.
  17. Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.
  18. Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia.
  1. Oncol Ther. 2019 Dec;7(2): 121-130
    Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1.
    Etienne Paubelle, Adriana Plesa, Sandrine Hayette, Mohamed Elhamri, Florence Zylbersztejn, Olivier Hermine, Gilles Salles, Xavier Thomas.
      INTRODUCTION: EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment.METHODS: In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1.
    RESULTS: Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool.
    CONCLUSION: These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.
    Keywords:  Acute myeloid leukemia; All-trans-retinoic acid; EVI1; Leukemia stem cells; MECOM
    DOI:  https://doi.org/10.1007/s40487-019-0095-9
  2. Cancers (Basel). 2020 Jul 16. pii: E1923. [Epub ahead of print]12(7):
    PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells.
    Nayoung Kim, Mi-Yeon Kim, Young-Uk Cho, WenYong Chen, Kyoo-Hyung Lee, Hun Sik Kim.
      The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38- leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concept that donor NK cell-based therapy is a viable strategy for overcoming TKI resistance in CML, particularly the advanced, multi-TKI-resistant CML with dismal outcome.
    Keywords:  blast crisis; chronic myeloid leukemia; leukemic stem cells; natural killer cells
    DOI:  https://doi.org/10.3390/cancers12071923
  3. Antioxidants (Basel). 2020 Jul 17. pii: E633. [Epub ahead of print]9(7):
    Targeting the MAPK/ERK and PI3K/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia Cells.
    Ewa Jasek-Gajda, Halina Jurkowska, Małgorzata Jasińska, Grzegorz J Lis.
      The mitogen-activated protein kinase (MAPK)/extracellular signal kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signal transduction pathways have been implicated in the pathogenesis of leukemia. The aim of this study was to investigate the effect of the combination of ERK1/2 inhibitor AZD0364 and PI3K inhibitor ZSTK474 on acute lymphoblastic leukemia (ALL) REH, MOLT-4, acute myeloid leukemia (AML) MOLM-14, and chronic myeloid leukemia (CML) K562 cell lines. To evaluate the interactions of the drugs, cells were treated for 48 h with AZD0364 or ZSTK474 alone and in combination at fixed ratios. The combinatorial effects of both inhibitors were synergistic over a wide range of concentrations in REH, MOLT-4, and MOLM-14 cell lines. However, in K562 cells, the effects were found to be antagonistic. Furthermore, AZD0364 and ZSTK474 significantly decreased both ERK1/2 and AKT activation in REH, MOLT-4, and MOLM-14 cells. The results showed that incubation with both AZD0364 and ZSTK474 inhibited cell viability, increased reactive oxygen species (ROS) production, and induced apoptosis in leukemia cells. We observed that combined treatment with AZD0364 and ZSTK474 affected nuclear factor-κB (NF-κB) and antioxidant protein levels: NF-E2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), thioredoxin (Trx), thioredoxin reductase (TrxR), and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. These effects were accompanied with decreased antiapoptotic survivin protein level. However, distinct cell line dependent effects were observed. In conclusion, the combination of AZD0364 and ZSTK474 can exert a synergistic anticancer effect in ALL and AML cells, which is associated with the induction of oxidative stress and the involvement of cellular antioxidant defense mechanisms.
    Keywords:  ERK; NRF2; PI3K; apoptosis; glutathione; leukemia; reactive oxygen species; thioredoxin
    DOI:  https://doi.org/10.3390/antiox9070633
  4. Hum Vaccin Immunother. 2020 Jul 21. 1-8
    Targeting the alpha subunit of IL-3 receptor (CD123) in patients with acute leukemia.
    Ibrahim Aldoss, Mary Clark, Joo Y Song, Vinod Pullarkat.
      The IL-3 alpha chain receptor (CD123) is a cell surface protein that is widely expressed by various subtypes of acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia and blastic plasmacytoid dendritic cell neoplasm. Notably, CD123 is preferentially overexpressed in leukemia stem cells (LSC) in contrast to normal hematopoietic stem cells, and this differential expression allows for the selective eradication of LSC and leukemic blasts through therapeutic targeting of CD123, with less impact on hematopoietic cells. The level of CD123 expression in AML correlates with both treatment response and outcomes. Therefore, targeting CD123 represents a promising universal therapeutic target in advanced acute leukemias irrespective of the individual leukemia phenotype. There are currently 31 ongoing clinical trials examining the utility of CD123-based targeted therapies. Here we focus our review on current efforts to target CD123 in acute leukemia through various therapeutic constructs.
    Keywords:  ALL; AML; BPDCN; CD123; Il3; bispecific antibody; flotetuzumab; tagraxofusp
    DOI:  https://doi.org/10.1080/21645515.2020.1788299
  5. Molecules. 2020 Jul 22. pii: E3325. [Epub ahead of print]25(15):
    Cell Growth Inhibition of Saponin XII from Dipsacus japonicus Miq. on Acute Myeloid Leukemia Cells.
    Ba Thi Cham, Nguyen Thi Thuy Linh, Do Thi Thao, Nguyen Thi Hoang Anh, Nguyen Thanh Tam, Bui Kim Anh, Isabella Muscari, Sabrina Adorisio, Tran Van Sung, Trinh Thi Thuy, Domenico V Delfino.
      In previous studies, we isolated the known compound saponin XII from the roots of Dipsacus japonicus Miq. Here, we show that this compound reduced the number of acute myeloid leukemia OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses demonstrated that the reported activity was associated with a significant increase of apoptosis and of cells in the G0/G1 phase of the cell cycle, with a decrease of cells in the S and G2/M phases. Thus, the inhibition of cell growth in OCI-AML3 cells was due to antiproliferative and pro-apoptotic effects. Interestingly, the bioactivity of saponin XII exerted its effect at a concentration as low as 1 µg/mL.
    Keywords:  Dipsacus japonicus Miq.; OCI-AML cells; antiproliferative activity; cancer; saponin XII
    DOI:  https://doi.org/10.3390/molecules25153325
  6. Nature. 2020 Jul 22.
    Signalling input from divergent pathways subverts B cell transformation.
    Lai N Chan, Mark A Murakami, Mark E Robinson, Rebecca Caeser, Teresa Sadras, Jaewoong Lee, Kadriye Nehir Cosgun, Kohei Kume, Vishal Khairnar, Gang Xiao, Mohamed A Ahmed, Eamon Aghania, Gauri Deb, Christian Hurtz, Seyedmehdi Shojaee, Chao Hong, Petri Pölönen, Matthew A Nix, Zhengshan Chen, Chun Wei Chen, Jianjun Chen, Andreas Vogt, Merja Heinäniemi, Olli Lohi, Arun P Wiita, Shai Izraeli, Huimin Geng, David M Weinstock, Markus Müschen.
      Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.
    DOI:  https://doi.org/10.1038/s41586-020-2513-4
  7. Cancers (Basel). 2020 Jul 16. pii: E1927. [Epub ahead of print]12(7):
    Genetic and Molecular Basis of Heterogeneous NK Cell Responses against Acute Leukemia.
    Dhon Roméo Makanga, Francesca Da Rin de Lorenzo, Gaëlle David, Catherine Willem, Léa Dubreuil, Nolwenn Legrand, Thierry Guillaume, Pierre Peterlin, Amandine Lebourgeois, Marie Christine Béné, Alice Garnier, Patrice Chevallier, Ketevan Gendzekhadze, Anne Cesbron, Katia Gagne, Béatrice Clemenceau, Christelle Retière.
      Natural killer (NK) cells are key cytotoxic effectors against malignant cells. Polygenic and polymorphic Killer cell Immunoglobulin-like Receptor (KIR) and HLA genes participate in the structural and functional formation of the NK cell repertoire. In this study, we extensively investigated the anti-leukemic potential of NK cell subsets, taking into account these genetic parameters and cytomegalovirus (CMV) status. Hierarchical clustering analysis of NK cell subsets based on NKG2A, KIR, CD57 and NKG2C markers from 68 blood donors identified donor clusters characterized by a specific phenotypic NK cell repertoire linked to a particular immunogenetic KIR and HLA profile and CMV status. On the functional side, acute lymphoblastic leukemia (ALL) was better recognized by NK cells than acute myeloid leukemia (AML). However, a broad inter-individual disparity of NK cell responses exists against the same leukemic target, highlighting bad and good NK responders. The most effective NK cell subsets against different ALLs expressed NKG2A and represented the most frequent subset in the NK cell repertoire. In contrast, minority CD57+ or/and KIR+ NK cell subsets were more efficient against AML. Overall, our data may help to optimize the selection of hematopoietic stem cell donors on the basis of immunogenetic KIR/HLA for ALL patients and identify the best NK cell candidates in immunotherapy for AML.
    Keywords:  CMV; HLA; KIR; acute leukemia; natural killer cells; repertoire
    DOI:  https://doi.org/10.3390/cancers12071927
  8. Leukemia. 2020 Jul 20.
    Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.
    Oliver Parting, Samantha Langer, Maja Kim Kuepper, Caroline Wessling, Shaoguang Li, Till Braunschweig, Nicolas Chatain, Tiago Maié, Ivan G Costa, Martina Crysandt, Michael Huber, Tim H Brümmendorf, Steffen Koschmieder, Mirle Schemionek.
      Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.
    DOI:  https://doi.org/10.1038/s41375-020-0977-8
  9. Leukemia. 2020 Jul 20.
    Prognostic value of monocyte subset distribution in chronic myelomonocytic leukemia: results of a multicenter study.
    Matthieu Jestin, Sihem Tarfi, Matthieu Duchmann, Bouchra Badaoui, Nicolas Freynet, Violaine Tran Quang, Ivan Sloma, Nathalie Droin, Margot Morabito, Mathieu Leclerc, Sébastien Maury, Pierre Fenaux, Eric Solary, Dorothée Selimoglu-Buet, Orianne Wagner-Ballon, .
      
    DOI:  https://doi.org/10.1038/s41375-020-0955-1
  10. Cancers (Basel). 2020 Jul 20. pii: E1972. [Epub ahead of print]12(7):
    Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML.
    Annalisa Lonetti, Valentina Indio, Maria Antonella Laginestra, Giuseppe Tarantino, Francesca Chiarini, Annalisa Astolfi, Salvatore N Bertuccio, Alberto M Martelli, Franco Locatelli, Andrea Pession, Riccardo Masetti.
      Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.
    Keywords:  BRAF; ChIP-seq; DOT1L; Pinometostat; Sorafenib; pediatric acute myeloid leukemia; targeted therapy
    DOI:  https://doi.org/10.3390/cancers12071972
  11. Nat Metab. 2020 Apr;2(4): 335-350
    Identifying strategies to target the metabolic flexibility of tumours.
    Andrés Méndez-Lucas, Wei Lin, Paul C Driscoll, Nathalie Legrave, Laura Novellasdemunt, Chencheng Xie, Mark Charles, Zena Wilson, Neil P Jones, Stephen Rayport, Manuel Rodríguez-Justo, Vivian Li, James I MacRae, Nissim Hay, Xin Chen, Mariia Yuneva.
      Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s42255-020-0195-8
  12. Haematologica. 2020 Jul 23. pii: haematol.2019.240754. [Epub ahead of print]
    Potential targeting of FLT3 AML.
    Alexander J Ambinder, Mark Levis.
      Aberrant FLT3 receptor signaling is common in acute myeloid leukemia (AML) and has important implications for the biology and clinical management of the disease. Patients with FLT3-mutated AML frequently present with critical illness, are more likely to relapse after treatment, and have worse clinical outcomes than their FLT3 wild type counterparts. The clinical management of FLT3-mutated AML has been transformed by the development of FLT3 inhibitors, which are now in use in the frontline and relapsed/refractory settings. However, many questions regarding the optimal approach to the treatment of these patients remain. In this paper, we will review the rationale for targeting the FLT3 receptor in AML, the impact of FLT3 mutation on patient prognosis, the current standard of care approaches to FLT3-mutated AML management, and the diverse array of FLT3 inhibitors in use and under investigation. We will also explore new opportunities and strategies for targeting the FLT3 receptor. These include targeting the receptor in patients with non-canonical FLT3 mutations or wild type FLT3, pairing FLT3 inhibitors with other novel therapies, using minimal residual disease (MRD) testing to guide the targeting of FLT3, and novel immunotherapeutic approaches.
    Keywords:  Acute Myeloid Leukemia; FLT3; TKI
    DOI:  https://doi.org/10.3324/haematol.2019.240754
  13. Nat Commun. 2020 Jul 20. 11(1): 3639
    Proteome activity landscapes of tumor cell lines determine drug responses.
    Martin Frejno, Chen Meng, Benjamin Ruprecht, Thomas Oellerich, Sebastian Scheich, Karin Kleigrewe, Enken Drecoll, Patroklos Samaras, Alexander Hogrebe, Dominic Helm, Julia Mergner, Jana Zecha, Stephanie Heinzlmeir, Mathias Wilhelm, Julia Dorn, Hans-Michael Kvasnicka, Hubert Serve, Wilko Weichert, Bernhard Kuster.
      Integrated analysis of genomes, transcriptomes, proteomes and drug responses of cancer cell lines (CCLs) is an emerging approach to uncover molecular mechanisms of drug action. We extend this paradigm to measuring proteome activity landscapes by acquiring and integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 CCLs. These data are used to contextualize proteins and p-sites and predict drug sensitivity. For example, we find that Progesterone Receptor (PGR) phosphorylation is associated with sensitivity to drugs modulating estrogen signaling such as Raloxifene. We also demonstrate that Adenylate kinase isoenzyme 1 (AK1) inactivates antimetabolites like Cytarabine. Consequently, high AK1 levels correlate with poor survival of Cytarabine-treated acute myeloid leukemia patients, qualifying AK1 as a patient stratification marker and possibly as a drug target. We provide an interactive web application termed ATLANTiC (http://atlantic.proteomics.wzw.tum.de), which enables the community to explore the thousands of novel functional associations generated by this work.
    DOI:  https://doi.org/10.1038/s41467-020-17336-9
  14. Cell Death Dis. 2020 Jul 20. 11(7): 552
    DDX5-targeting fully human monoclonal autoantibody inhibits proliferation and promotes differentiation of acute promyelocytic leukemia cells by increasing ROS production.
    Jing Wu, Yan-Qiu You, Yan-Xiu Ma, Yan-Hua Kang, Tian Wu, Xiang-Ji Wu, Xiao-Xiao Hu, Qiao-Hong Meng, Yin Huang, Na Zhang, Xiao-Ben Pan.
      Acute promyelocytic leukemia (APL) therapy involves the compounds cytotoxic to both malignant tumor and normal cells. Relapsed APL is resistant to subsequent chemotherapy. Novel agents are in need to kill APL cells selectively with minimal toxicity. DDX5 has been recognized to be a novel target to suppress acute myeloid leukemia (AML). However, the role of DDX5 remains elusive in APL. Here a DDX5-targeting fully human monoclonal autoantibody named after 2F5 was prepared. It is demonstrated that 2F5 selectively inhibited APL cell proliferation without toxicity to normal neutrophil and tissues. Moreover, 2F5 was confirmed to induce G0/G1 phase arrest in APL cells, and promote APL cell differentiation combined with decreased DDX5 expression and increased reactive oxygen species (ROS) production. Knockdown of DDX5 by siRNA also inhibited proliferation, promoted cell differentiation and enhanced ROS production in APL cells. However, the ROS inhibitor reversed the effects of 2F5 on DDX5 and ROS in APL cells. Thus, we conclude that DDX5-targeting 2F5 inhibits APL cell proliferation, and promotes cell differentiation via induction of ROS. 2F5 showed the therapeutic value of fully human monoclonal autoantibody in APL, which provides a novel and valid approach for treatment of relapse/refractory APL.
    DOI:  https://doi.org/10.1038/s41419-020-02759-5
  15. J Clin Oncol. 2020 Jul 20. JCO2000572
    Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy.
    Chong Chyn Chua, Andrew W Roberts, John Reynolds, Chun Yew Fong, Stephen B Ting, Jessica M Salmon, Sarah MacRaild, Adam Ivey, Ing Soo Tiong, Shaun Fleming, Fiona C Brown, Sun Loo, Ian J Majewski, Stefan K Bohlander, Andrew H Wei.
      PURPOSE: The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown.PATIENTS AND METHODS: Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days -6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2.
    RESULTS: Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML.
    CONCLUSION: Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).
    DOI:  https://doi.org/10.1200/JCO.20.00572
  16. Technol Cancer Res Treat. 2020 Jan-Dec;19:19 1533033820942312
    PPM1D Knockdown Suppresses Cell Proliferation, Promotes Cell Apoptosis, and Activates p38 MAPK/p53 Signaling Pathway in Acute Myeloid Leukemia.
    Bin Li, Jie Hu, Di He, Qi Chen, Suna Liu, Xiaoling Zhu, Meijia Yu.
      OBJECTIVES: This study was to explore the effect of protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown on proliferation and apoptosis as well as p38 MAPK/p53 signaling pathway in acute myeloid leukemia.METHODS: The expression of protein phosphatase, Mg2+/Mn2+ dependent 1D was detected in acute myeloid leukemia cell lines including SKM-1, KG-1, AML-193, and THP-1 cells, and normal bone marrow mononuclear cells isolated from healthy donors. The knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D was conducted by transfecting small interfering RNA into AML-193 cells and KG-1 cells.
    RESULTS: The relative messenger RNA/protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were higher in SKM-1, KG-1, AML-193, and THP-1 cells compared with control cells (normal bone marrow mononuclear cells). After transfecting protein phosphatase, Mg2+/Mn2+ dependent 1D small interfering RNA into AML-193 cells and KG-1 cells, both messenger RNA and protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were significantly reduced, indicating the successful transfection. Most importantly, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D suppressed cell proliferation and promoted cell apoptosis in AML-193 cells and KG-1 cells. In addition, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D enhanced the expressions of p-p38 and p53 in AML-193 cells and KG-1 cells. The above observation suggested that protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown suppressed cell proliferation, promoted cell apoptosis, and activated p38 MAPK/p53 signaling pathway in acute myeloid leukemia cells.
    CONCLUSION: Protein phosphatase, Mg2+/Mn2+ dependent 1D is implicated in acute myeloid leukemia carcinogenesis, which illuminates its potential role as a treatment target for acute myeloid leukemia.
    Keywords:  AML; PPM1D; apoptosis; p38 MAPK/p53 signaling pathway; proliferation
    DOI:  https://doi.org/10.1177/1533033820942312
  17. Sci Rep. 2020 Jul 21. 10(1): 12027
    Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.
    Kendra R Vann, Dhananjaya Pal, Guillermo A Morales, Adam M Burgoyne, Donald L Durden, Tatiana G Kutateladze.
      Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.
    DOI:  https://doi.org/10.1038/s41598-020-68964-6
  18. Sci Rep. 2020 Jul 22. 10(1): 12152
    Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia.
    Shujuan Wang, Zhenzhen Wu, Tao Li, Yafei Li, Weiqiong Wang, Qianqian Hao, Xinsheng Xie, Dingming Wan, Zhongxing Jiang, Chong Wang, Yanfang Liu.
      The mutational spectrum and prognostic factors of NRAS-mutated (NRASmut) acute myeloid leukemia (AML) are largely unknown. We performed next-generation sequencing (NGS) in 1,149 cases of de novo AML and discovered 152 NRASmut AML (13%). Of the 152 NRASmut AML, 89% had at least one companion mutated gene. DNA methylation-related genes confer up to 62% incidence. TET2 had the highest mutation frequency (51%), followed by ASXL1 (17%), NPM1 (14%), CEBPA (13%), DNMT3A (13%), FLT3-ITD (11%), KIT (11%), IDH2 (9%), RUNX1 (8%), U2AF1 (7%) and SF3B1(5%). Multivariate analysis suggested that age ≥ 60 years and mutations in U2AF1 were independent factors related to failure to achieve complete remission after induction therapy. Age ≥ 60 years, non-M3 types and U2AF1 mutations were independent prognostic factors for poor overall survival. Age ≥ 60 years, non-M3 types and higher risk group were independent prognostic factors for poor event-free survival (EFS) while allogenic hematopoietic stem cell transplantation was an independent prognostic factor for good EFS. Our study provided new insights into the mutational spectrum and prognostic factors of NRASmut AML.
    DOI:  https://doi.org/10.1038/s41598-020-69194-6
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