bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020–11–22
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia.
  2. AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.
  3. CC-90009, a novel cereblon E3 ligase modulator targets acute myeloid leukemia blasts and leukemia stem cells.
  4. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia.
  5. Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments.
  6. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.
  7. Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin.
  8. Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway.
  9. A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.
  10. Apoptosis targeted therapies in acute myeloid leukemia: an update.
  11. XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature.
  12. Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia.
  13. Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia.
  14. ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation.
  15. The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis.
  16. Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience.
  17. SF3B1-mutant CMML defines a predominantly dysplastic CMML subtype with a superior acute leukemia-free survival.
  18. MLL-menin and FLT3 inhibitors team up for AML.
  19. Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia.
  20. Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes.
  21. Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model.
  22. Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor.
  23. Tyrosine kinase inhibitor discontinuation in the management of chronic myeloid leukemia: a critical review of the current practice.
  1. Cell Rep Med. 2020 Aug 25. 1(5): 100074
    Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia.
    Patricia A Olofsen, Szabolcs Fatrai, Paulina M H van Strien, Julia C Obenauer, Hans W J de Looper, Remco M Hoogenboezem, Claudia A J Erpelinck-Verschueren, Michael P W M Vermeulen, Onno Roovers, Torsten Haferlach, Joop H Jansen, Mehrnaz Ghazvini, Eric M J Bindels, Rebekka K Schneider, Emma M de Pater, Ivo P Touw.
      Severe congenital neutropenia (SCN) patients treated with CSF3/G-CSF to alleviate neutropenia frequently develop acute myeloid leukemia (AML). A common pattern of leukemic transformation involves the appearance of hematopoietic clones with CSF3 receptor (CSF3R) mutations in the neutropenic phase, followed by mutations in RUNX1 before AML becomes overt. To investigate how the combination of CSF3 therapy and CSF3R and RUNX1 mutations contributes to AML development, we make use of mouse models, SCN-derived induced pluripotent stem cells (iPSCs), and SCN and SCN-AML patient samples. CSF3 provokes a hyper-proliferative state in CSF3R/RUNX1 mutant hematopoietic progenitors but does not cause overt AML. Intriguingly, an additional acquired driver mutation in Cxxc4 causes elevated CXXC4 and reduced TET2 protein levels in murine AML samples. Expression of multiple pro-inflammatory pathways is elevated in mouse AML and human SCN-AML, suggesting that inflammation driven by downregulation of TET2 activity is a critical step in the malignant transformation of SCN.
    Keywords:  AML; CSF3R; CXXC4; RUNX1; TET2; growth factor therapy; leukemia predisposition; pro-inflammatory signaling; severe congenital neutropenia
    DOI:  https://doi.org/10.1016/j.xcrm.2020.100074
  2. Oncogene. 2020 Nov 17.
    AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.
    Ita Novita Sari, Ying-Gui Yang, Yoseph Toni Wijaya, Nayoung Jun, Sanghyun Lee, Kwang Seock Kim, Jeevisha Bajaj, Vivian G Oehler, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Tannishtha Reya, Jaeseok Han, Hyog Young Kwon.
      Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.
    DOI:  https://doi.org/10.1038/s41388-020-01547-x
  3. Blood. 2020 Nov 16. pii: blood.2020008676. [Epub ahead of print]
    CC-90009, a novel cereblon E3 ligase modulator targets acute myeloid leukemia blasts and leukemia stem cells.
    Christine Surka, Liqing Jin, Nathan Mbong, Chin-Chun Lu, In Sock Jang, Emily Rychak, Derek Mendy, Thomas Clayton, Elizabeth Anne Tindall, Christy Hsu, Celia Fontanillo, Eileen Tran, Adrian Contreras, Stanley Wai-Kwong Ng, Mary Ellen Matyskiela, Kai Wang, Philip P Chamberlain, Brian Cathers, James Carmichael, Joshua D Hansen, Jean C Y Wang, Mark D Minden, Jinhong Fan, Daniel W Pierce, Michael Pourdehnad, Mark Rolfe, Antonia Lopez-Girona, John E Dick, Gang Lu.
      A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural and molecular characterization demonstrates that CC-90009 co-opts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces AML apoptosis, reducing leukemia engraftment and leukemia stem cells (LSC) in large scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN mRNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response (ISR) specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009 induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSC, whose elucidation gives insight into further assessment of CC-90009's clinical utility.
    DOI:  https://doi.org/10.1182/blood.2020008676
  4. Blood Adv. 2020 Nov 24. 4(22): 5681-5689
    Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia.
    Nicholas J Short, Guillermo Montalban-Bravo, Hyunsoo Hwang, Jing Ning, Miguel J Franquiz, Rashmi Kanagal-Shamanna, Keyur P Patel, Courtney D DiNardo, Farhad Ravandi, Guillermo Garcia-Manero, Koichi Takahashi, Marina Konopleva, Naval Daver, Ghayas C Issa, Michael Andreeff, Hagop Kantarjian, Tapan M Kadia.
      TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 (TP53mut) variant allelic frequency (VAF) is not well established, nor is how this information might guide optimal frontline therapy. We retrospectively analyzed 202 patients with newly diagnosed TP53-mutated AML who underwent first-line therapy with either a cytarabine- or hypomethylating agent (HMA)-based regimen. By multivariate analysis, TP53mut VAF >40% was independently associated with a significantly higher cumulative incidence of relapse (P = .003) and worse relapse-free survival (P = .001) and overall survival (OS; P = .003). The impact of TP53mut VAF on clinical outcomes was driven by patients treated with a cytarabine-based regimen (median OS, 4.7 vs 7.3 months for VAF >40% vs ≤40%; P = .006), whereas VAF did not significantly affect OS in patients treated with HMA. The addition of venetoclax to HMA did not significantly affect OS compared with HMA without venetoclax, both in the entire TP53-mutated population and in patients stratified by TP53mut VAF. Among patients with TP53mut VAF ≤40%, OS was superior in those treated with higher-dose cytarabine, whereas OS was similarly poor for patients with TP53mut VAF >40% regardless of therapy. The best long-term outcomes were observed in those with 1 TP53 mutation with VAF ≤40% who received a frontline cytarabine-based regimen (2-year OS, 38% vs 6% for all others; P < .001). In summary, TP53mut VAF provides important prognostic information that may be considered when selecting frontline therapy for patients with newly diagnosed TP53-mutated AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003120
  5. Cells. 2020 Nov 17. pii: E2493. [Epub ahead of print]9(11):
    Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments.
    Sebastian Scholl, Maximilian Fleischmann, Ulf Schnetzke, Florian H Heidel.
      Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.
    Keywords:  AML; FLT3; FLT3-ITD; FLT3-TKD; FMS-like tyrosine kinase 3; acute myeloid leukemia; crenolanib; gilteritinib; midostaurin; quizartinib; resistance
    DOI:  https://doi.org/10.3390/cells9112493
  6. Leukemia. 2020 Nov 16.
    Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.
    Ashkan Emadi, Bandish Kapadia, Dominique Bollino, Binny Bhandary, Maria R Baer, Sandrine Niyongere, Erin T Strovel, Hannah Kaizer, Elizabeth Chang, Eun Yong Choi, Xinrong Ma, Kayla M Tighe, Brandon Carter-Cooper, Blake S Moses, Curt I Civin, Anup Mahurkar, Amol C Shetty, Ronald B Gartenhaus, Farin Kamangar, Rena G Lapidus.
      Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.
    DOI:  https://doi.org/10.1038/s41375-020-01080-6
  7. Blood Adv. 2020 Nov 24. 4(22): 5735-5744
    Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin.
    Bridget K Marcellino, Noushin Farnoud, Bruno Cassinat, Min Lu, Emanuelle Verger, Erin McGovern, Minal Patel, Juan Medina-Martinez, Max Fine Levine, Juanes E Arango Ossa, Yangyu Zhou, Heidi Kosiorek, Meenakshi Mehrotra, Jane Houldsworth, Amylou Dueck, Michael Rossi, John Mascarenhas, Jean-Jacques Kiladjian, Raajit K Rampal, Ronald Hoffman.
      Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002379
  8. Front Pharmacol. 2020 ;11 569651
    Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway.
    Liman Lin, Yimei Que, Pingfan Lu, Huimin Li, Min Xiao, Xiaojian Zhu, Dengju Li.
      Irregular histone modification and aberrant lncRNAs expression are closely related to the occurrence of tumors including acute myeloid leukemia (AML). However, the effects and specific underlying molecular mechanism of histone deacetylase inhibitors on lncRNA expression in AML cells are unclear. Here, we reported the effects of a novel histone deacetylase inhibitor Chidamide on proliferation and lncRNA expression in AML cells. Chidamide inhibited cell proliferation, blocked G1/S phase transition, and induced cell apoptosis through the caspase-dependent apoptotic pathway in AML cells. Chidamide also inhibited the formation of subcutaneous tumors. Transcriptome sequencing results showed that 1,195 lncRNAs were co-upregulated and 780 lncRNAs were co-downregulated after Chidamide treatment of SKM-1 cells and THP-1 cells. Combined with transcriptome sequencing data and the gene expression profiling interactive analysis dataset, we found that VPS9D1-AS1 expression was negatively correlated with the survival of AML patients. VPS9D1-AS1 knockdown inhibited cell proliferation, arrested cell cycle, as well as inhibited the formation of subcutaneous tumors in vivo. VPS9D1-AS1 overexpression had the reverse effect. Furthermore, VPS9D1-AS1 knockdown inhibited the MEK/ERK signaling pathway, and thus enhanced the inhibitory effect of Chidamide on AML cell proliferation. These findings suggested that targeted regulation of VPS9D1-AS1 might overcome the limitations of Chidamide in the treatment of AML.
    Keywords:  MEK/ERK signaling pathway; VPS9D1-AS1; acute myeloid leukemia; chidamide; long non-coding RNA; proliferation
    DOI:  https://doi.org/10.3389/fphar.2020.569651
  9. Front Oncol. 2020 ;10 587062
    A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.
    Alexander J Ambinder, Kelly Norsworthy, Daniela Hernandez, Laura Palau, Bogdan Paun, Amy Duffield, Rosh Chandraratna, Martin Sanders, Ravi Varadhan, Richard J Jones, B Douglas Smith, Gabriel Ghiaur.
      Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.
    Keywords:  acute myeloid leukemia; differentiation therapy; microenvironment niche; phase 1 clinical trial; retinoic acid receptor agonist
    DOI:  https://doi.org/10.3389/fonc.2020.587062
  10. Expert Rev Hematol. 2020 Nov 18.
    Apoptosis targeted therapies in acute myeloid leukemia: an update.
    Somedeb Ball, Gautam Borthakur.
       INTRODUCTION: Management of acute myeloid leukemia (AML) continues to be a therapeutic challenge despite significant recent advancements. Dysregulation of several components of apoptotic pathways has been identified as potential driver in AML.
    AREAS COVERED: Overexpression of anti-apoptotic proteins, B-cell lymphoma 2 (BCL2), Bcl-xL, and myeloid cell leukemia-1 (MCL1), has been associated with worse outcome in AML. Dysfunction of p53 pathway (often through mouse double minute 2 homolog (MDM2)) and high expression of inhibitor of apoptosis proteins (IAP) constitute other disruptions of apoptotic machinery. Significant antileukemic activity of BCL2 inhibitors (particularly venetoclax) in preclinical models has translated into improved objective response and overall survival in combination with hypomethylating agents in AML. Addition of MCL1, BCL-XL or MDM2 inhibitors could potentially overcome resistance to BCL2 inhibition. Authors conducted a thorough review of available literature on therapeutic options targeting apoptosis in AML, using PubMed, MEDLINE, meeting abstracts, and ClinicalTrials.gov.
    EXPERT OPINION: While venetoclax remains the core component of targeting apoptosis, ongoing clinical trials should help find ideal combination regimens in different AML subgroups. Future research should focus on overcoming resistance to BCL2 inhibition, optimal management of adverse events and development of biomarkers to identify patients most likely to benefit from apoptosis- targeted therapies.
    Keywords:  APR-246; Acute Myeloid Leukemia; BCL2; Intrinsic Pathway; MDM2; Venetoclax
    DOI:  https://doi.org/10.1080/17474086.2020.1852923
  11. Nat Commun. 2020 11 17. 11(1): 5834
    XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature.
    Andrey A Yurchenko, Ismael Padioleau, Bakhyt T Matkarimov, Jean Soulier, Alain Sarasin, Sergey Nikolaev.
      Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.
    DOI:  https://doi.org/10.1038/s41467-020-19633-9
  12. Cancer Cell. 2020 Nov 18. pii: S1535-6108(20)30541-9. [Epub ahead of print]
    Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia.
    Shruti Bhatt, Marissa S Pioso, Elyse Anne Olesinski, Binyam Yilma, Jeremy A Ryan, Thelma Mashaka, Buon Leutz, Sophia Adamia, Haoling Zhu, Yanan Kuang, Abhishek Mogili, Abner J Louissaint, Stephan R Bohl, Annette S Kim, Anita K Mehta, Sneha Sanghavi, Youzhen Wang, Erick Morris, Ensar Halilovic, Cloud P Paweletz, David M Weinstock, Jacqueline S Garcia, Anthony Letai.
      Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to BCL-2 (venetoclax) and MCL-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in BCL-2 family proteins that vary among cases, but not to acquired mutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.
    Keywords:  BCL-2; BH3 mimetics; BH3 profiling; FLT-3; MCL-1; SMAC; leukemia; mitochondria; precision cancer medicine; venetoclax
    DOI:  https://doi.org/10.1016/j.ccell.2020.10.010
  13. Int J Mol Sci. 2020 Nov 12. pii: E8505. [Epub ahead of print]21(22):
    Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia.
    Carmelo Gurnari, Simona Pagliuca, Valeria Visconte.
      Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40-60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies' (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness.
    Keywords:  acute myeloid leukemia; chemotherapy resistance; hypomethylating agent resistance
    DOI:  https://doi.org/10.3390/ijms21228505
  14. Bone Marrow Transplant. 2020 Nov 19.
    ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation.
    Madlen Jentzsch, Juliane Grimm, Marius Bill, Dominic Brauer, Donata Backhaus, Karoline Goldmann, Julia Schulz, Dietger Niederwieser, Uwe Platzbecker, Sebastian Schwind.
      Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.
    DOI:  https://doi.org/10.1038/s41409-020-01129-1
  15. Hematology. 2020 Dec;25(1): 414-423
    The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis.
    Bei Liu, Yuancheng Guo, Lijuan Deng, Yanhong Qiao, Jinli Jian.
       OBJECTIVES: To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS).
    METHODS: Clinical studies were identified from the Cochrane Library, PubMed, Embase, Google Scholar, and ClinicalTrials.gov. Overall complete remission (CR) and overall response rate (ORR) were used to evaluate the efficacy of VEN in combination with HMAs for AML/MDS, the incidence of the 4 most common grade 3-4 adverse events was used to evaluate safety.
    RESULTS: We identified 13 studies that included a total of 1059 patients. 7 cohort studies and 5 non-randomized controlled trials(NRCTs) were analyzed by random-effects model, and subgroup analyses showed the pooled overall CR rate of 62% (95% CI 57-67%, I2 = 3%) for the new-diagnosed(ND) AML group, 39% (95% CI 30-48%, I2 = 28%) for relapsed/refractory(R/R)-AML, and 61% (95% CI 50-71%, I2 = 25%) for MDS, respectively. There was only one randomized controlled trial(RCT) that showed a CR rate of 66.4% in the patients who received azacitidine(AZA) plus VEN. A total of 8 studies reported adverse events, with cytopenia and infection being the most common grade 3-4 adverse events.
    CONCLUSIONS: The addition of VEN to HMAs may provide significant clinical benefit for AML/MDS patients, where response rates are better in MDS and ND-AML than in R/R-AML, but attention should be paid to the possible increased risk of febrile neutropenia.
    Keywords:  Acute myeloid leukemia; hypomethylating agent; myelodysplastic syndrome; venetoclax
    DOI:  https://doi.org/10.1080/16078454.2020.1843752
  16. Int J Hematol. 2020 Nov 20.
    Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience.
    Naoko Hosono, Miyuki Ookura, Hiroaki Araie, Mihoko Morita, Kazuhiro Itoh, Yasufumi Matsuda, Takahiro Yamauchi.
      We retrospectively evaluated the clinical efficacy and toxicity of gemtuzumab ozogamicin (GO) in patients with relapsed acute myeloid leukemia (AML). Nineteen patients (median 70 years) received GO (9 mg/m2, days 1 and 15) as salvage therapy in our institution between 2006 and 2017. The primary endpoint was the response rate. The secondary endpoint was the occurrence of adverse events. Thirteen patients had de novo AML, and 6 patients had secondary AML. Most of the patients had received salvage treatments more than once prior to GO. Six patients responded to the treatment (31.6%) with 3 complete remissions (15.8%). Five patients had stable disease, and 8 patients did not show any response. GO was more efficacious among the patients with fewer numbers of prior salvage treatments. CD33 positivity of leukemic cells was higher in responders than in nonresponders. Peripheral WT1 mRNA levels mostly decreased over time in the responders. The adverse event most commonly seen was febrile neutropenia (84%). No patient presented with veno-occlusive disease. Three patients died by day 30 (mortality rate 15.8%), one due to acute respiratory distress syndrome and the other two due to sepsis. GO remains an effective salvage treatment.
    Keywords:  Acute myeloid leukemia (AML); Gemtuzumab ozogamicin (GO); Relapsed; Wilms Tumor 1 (WT1)
    DOI:  https://doi.org/10.1007/s12185-020-03023-4
  17. Blood Adv. 2020 Nov 24. 4(22): 5716-5721
    SF3B1-mutant CMML defines a predominantly dysplastic CMML subtype with a superior acute leukemia-free survival.
    Kitsada Wudhikarn, Sanam Loghavi, Abhishek A Mangaonkar, Aref Al-Kali, Moritz Binder, Ryan Carr, Kaaren Reichard, Christy Finke, Matthew Howard, Naseema Gangat, Ayalew Tefferi, Rami Komrokji, Najla Ali, Terra Lasho, Rhett Ketterling, Eric Padron, Mrinal M Patnaik.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2020003345
  18. Blood. 2020 Nov 19. 136(21): 2369-2370
    MLL-menin and FLT3 inhibitors team up for AML.
    Alexander E Perl.
      
    DOI:  https://doi.org/10.1182/blood.2020007671
  19. J Hematol Oncol. 2020 Nov 19. 13(1): 155
    Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia.
    Melat T Gebru, Hong-Gang Wang.
      Acute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.
    Keywords:  AML; Drug resistance; Drug tolerance; FLT3
    DOI:  https://doi.org/10.1186/s13045-020-00992-1
  20. Cell Death Dis. 2020 Nov 20. 11(11): 997
    Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes.
    Jing-Dong Zhou, Ting-Juan Zhang, Zi-Jun Xu, Zhao-Qun Deng, Yu Gu, Ji-Chun Ma, Xiang-Mei Wen, Jia-Yan Leng, Jiang Lin, Su-Ning Chen, Jun Qian.
      The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression.
    DOI:  https://doi.org/10.1038/s41419-020-03213-2
  21. Leukemia. 2020 Nov 16.
    Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model.
    Toshihiro Tomii, Toshihiko Imamura, Kuniaki Tanaka, Itaru Kato, Azusa Mayumi, Emi Soma, Mio Yano, Kenichi Sakamoto, Takashi Mikami, Makiko Morita, Nobutaka Kiyokawa, Keizo Horibe, Souichi Adachi, Tatsutoshi Nakahata, Junko Takita, Hajime Hosoi.
      
    DOI:  https://doi.org/10.1038/s41375-020-01091-3
  22. Blood. 2020 Nov 17. pii: blood.2020006264. [Epub ahead of print]
    Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor.
    Ruochen Jia, Thomas Balligand, Vasyl Atamanyuk, Harini Nivarthi, Erica Xu, Leon Kutzner, Jakob Weinzierl, Audrey Nedelec, Stefan Kubicek, Roman Lesyk, Oleh Zagrijtschuk, Stefan N Constantinescu, Robert Kralovics.
      Somatic mutations of calreticulin (CALR)have been identified as one of the main disease drivers of myeloproliferative neoplasms (MPNs), suggesting that developing drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD)abolishes the ability of mutant CALRto oncogenically activate the thrombopoietin receptor (MPL).We thus hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in-silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing selective growth inhibitory effect on cells that depend on oncogenic CALRs for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR mutated cells than in CALR wild type cells. Additionally, knockout or C-terminal truncation of CALR abolished the drug hypersensitivity in CALR mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, the disruption of the mutant CALR-MPL interaction, the inhibition of the JAK2-STAT5 pathway, and reduction of intracellular level of mutant CALR upon the drug treatment. Our data conclude that small molecules targeting the GBD of CALR can selectively kill CALR mutated cells by disrupting the CALR-MPL interaction and inhibiting the oncogenic signaling.
    DOI:  https://doi.org/10.1182/blood.2020006264
  23. Expert Rev Hematol. 2020 Nov 18.
    Tyrosine kinase inhibitor discontinuation in the management of chronic myeloid leukemia: a critical review of the current practice.
    Massimo Breccia, Fabio Efficace, Gioia Colafigli, Emilia Scalzulli, Alessio Di Prima, Maurizio Martelli, Robin Foà.
      Introduction: Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. Areas covered: In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. Expert opinion: With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR.
    Keywords:  Chronic myeloid leukemia; deep molecular response; discontinuation; monitoring; relapse; treatment-free remission; tyrosine-kinase inhibitors
    DOI:  https://doi.org/10.1080/17474086.2021.1852924
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