bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒09‒20
nineteen papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Somatic mutations drive specific, but reversible epigenetic heterogeneity states in AML.
  2. Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis.
  3. Targeting neurolysin in acute myeloid leukemia.
  4. Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia.
  5. IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis.
  6. Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells.
  7. The Incidence of Invasive Fungal Infections in Patients With AML Treated With a Hypomethylating Agent.
  8. Identification of Long Non-Coding RNA SNHG Family as Promising Prognostic Biomarkers in Acute Myeloid Leukemia.
  9. Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence.
  10. Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.
  11. The impact of cytogenetic risk on the outcomes of Allogeneic Hematopoietic Cell Transplantation in patients with relapsed/refractory acute myeloid leukemia: on behalf of the Acute Leukemia Working Party (ALWP) of the EBMT.
  12. Conjugation of TLR7 Agonist Combined with Demethylation Treatment Improves Whole-Cell Tumor Vaccine Potency in Acute Myeloid Leukemia.
  13. Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase 3, Randomized, Open-label, Multi-center FESTnd Study.
  14. Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.
  15. RAD52 aptamer regulates DNA damage repair and STAT3 in BRCA1/BRCA2‑deficient human acute myeloid leukemia.
  16. METTL6 is a tRNA m3C methyltransferase that regulates pluripotency and tumor cell growth.
  17. Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia.
  18. Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development.
  19. RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development.
  1. Cancer Discov. 2020 Sep 16. pii: CD-19-0897. [Epub ahead of print]
    Somatic mutations drive specific, but reversible epigenetic heterogeneity states in AML.
    Sheng Li, Xiaowen Chen, Jiahui Wang, Cem Meydan, Jacob L Glass, Alan H Shih, Ruud Delwel, Ross L Levine, Christopher E Mason, Ari M Melnick.
      Epigenetic allele diversity is linked to inferior prognosis in acute myeloid leukemia (AML). However, the source of epiallele heterogeneity in AML is unknown. Herein we analyzed epiallele diversity in a genetically and clinically annotated AML cohort. Notably, AML driver mutations linked to transcription factors and favorable outcome are associated with epigenetic destabilization in a defined set of susceptible loci. In contrast AML subtypes linked to inferior prognosis manifest greater abundance and highly stochastic epiallele patterning. We report an epiallele outcome classifier supporting the link between epigenetic diversity and treatment failure. Mouse models with TET2 or IDH2 mutations show that epiallele diversity is especially strongly induced by IDH mutations, precedes transformation to AML, and is enhanced by cooperation between somatic mutations. Furthermore, epiallele complexity was partially reversed by epigenetic therapies in AML driven by TET2/IDH2, suggesting that epigenetic therapy might function in part by reducing population complexity and fitness of AMLs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-0897
  2. EMBO J. 2020 Sep 18. e105111
    Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis.
    Eric P Kusnadi, Anna S Trigos, Carleen Cullinane, David L Goode, Ola Larsson, Jennifer R Devlin, Keefe T Chan, David P De Souza, Malcolm J McConville, Grant A McArthur, George Thomas, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Katherine M Hannan, Jian Kang, Richard B Pearson.
      Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.
    Keywords:  RNA Polymerase I inhibitor; cAMP-EPAC1/2 pathway; hematological cancers; metformin; ribosome biogenesis and function
    DOI:  https://doi.org/10.15252/embj.2020105111
  3. Mol Cell Oncol. 2020 ;7(4): 1761243
    Targeting neurolysin in acute myeloid leukemia.
    Sara Mirali, Aaron D Schimmer.
      We recently identified the mitochondrial peptidase, neurolysin (NLN), as a top hit in an acute myeloid leukemia (AML) viability screen. Using chemical and genetic approaches, we demonstrated that loss of NLN disrupted respiratory chain supercomplex assembly and impaired oxidative metabolism in AML. Moreover, inhibition of NLN in vitro and in vivo reduced the growth of AML cells.
    Keywords:  Acute myeloid leukemia; LETM1; metabolism; neurolysin; respiratory chain supercomplexes
    DOI:  https://doi.org/10.1080/23723556.2020.1761243
  4. Blood Cancer Discov. 2020 Sep;1(2): 198-213
    Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia.
    Tian Zhang, Jiawen Yang, Vijaya P Vaikari, John S Beckford, Sharon Wu, Mojtaba Akhtari, Houda Alachkar.
      Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is significantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is significantly associated with decreased OS (HR: 2.51; 95% CI, 1.03-6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN-ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro, and delays leukemia progression in mice. Altogether, this study establishes APOC2-CD36 axis as a potential therapeutic target in AML.
    DOI:  https://doi.org/10.1158/2643-3230.bcd-19-0077
  5. Leukemia. 2020 Sep 18.
    IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis.
    Badder Kattih, Amir Shirvani, Piroska Klement, Abel Martin Garrido, Razif Gabdoulline, Alessandro Liebich, Maximilian Brandes, Anuhar Chaturvedi, Timon Seeger, Felicitas Thol, Gudrun Göhring, Brigitte Schlegelberger, Robert Geffers, David John, Udo Bavendiek, Johann Bauersachs, Arnold Ganser, Joerg Heineke, Michael Heuser.
      Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (p < 0.001) vs 58.5% to 55.4% (p = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation of IDH1/2 mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.
    DOI:  https://doi.org/10.1038/s41375-020-01043-x
  6. Oncol Rep. 2020 Aug 11.
    Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells.
    Roberta Napolitano, Serena De Matteis, Silvia Carloni, Samantha Bruno, Giulia Abbati, Laura Capelli, Martina Ghetti, Maria Teresa Bochicchio, Chiara Liverani, Laura Mercatali, Daniele Calistri, Antonio Cuneo, Krishna Menon, Gerardo Musuraca, Giovanni Martinelli, Giorgia Simonetti.
      Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53‑dependent as well as‑independent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wild‑type: OCI‑AML3 and MOLM‑13; and TP53‑mutant: KASUMI‑1 and NOMO‑1) to kevetrin at a concentration range of 85‑340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin V‑propidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wild‑type cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53‑mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wild‑type and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild‑type and TP53‑mutant AML.
    DOI:  https://doi.org/10.3892/or.2020.7730
  7. Clin Lymphoma Myeloma Leuk. 2020 Aug 21. pii: S2152-2650(20)30429-8. [Epub ahead of print]
    The Incidence of Invasive Fungal Infections in Patients With AML Treated With a Hypomethylating Agent.
    Michael Ozga, Ying Huang, James S Blachly, Nicole R Grieselhuber, Sarah Wall, Karilyn Larkin, Tamanna Haque, Alison R Walker, Bhavana Bhatnagar, Gregory Behbehani, Sumithira Vasu, Joseph E Maakaron, Mark Lustberg, Alice S Mims.
      BACKGROUND: Newly diagnosed patients with acute myeloid leukemia (AML) who receive induction with a hypomethylating agent (HMA) are often neutropenic with an increased risk for invasive fungal infections (IFIs). This study analyzed the incidence and risk factors for IFIs in these patients, evaluated clinical patterns in antifungal prophylaxis, and assessed the diagnostic utility of tests in this setting.PATIENTS AND METHODS: We studied 117 newly diagnosed patients with AML treated with HMAs at our center, divided into groups based on concern for IFI (cIFI: all possible, probable, and proven IFIs) versus no concern for IFI. The Fisher exact test compared patients with cIFI versus without, and a multivariable logistic regression model estimated odds for cIFI.
    RESULTS: Sixty-seven (57%) patients had cIFI, with 48 possible IFIs, 17 probable, and 2 proven cases. There was no difference in incidence based on home zip code, but the presence of chronic obstructive pulmonary disease was highly associated with cIFI (P = .001), as was male gender (P = .01). Neutropenia at treatment initiation was borderline in significance (P = .08). In diagnostics, 9% of patients had positive serum fungal markers, and 30 patients underwent bronchoscopy, with only 27% of cases yielding positive results. There was a difference in treatment regimens between patients receiving antifungal prophylaxis with mold coverage versus without mold coverage with respect to cIFI (P = .04).
    CONCLUSIONS: cIFI in patients with AML treated with HMAs remains significant, especially in males and those with chronic obstructive pulmonary disease, who were found to be at higher risk. This may prompt clinicians to consider anti-mold prophylaxis in this setting.
    Keywords:  Acute myeloid leukemia; Anti-mold azoles; Antifungal prophylaxis; Decitabine; Risk stratification
    DOI:  https://doi.org/10.1016/j.clml.2020.08.013
  8. Onco Targets Ther. 2020 ;13 8441-8450
    Identification of Long Non-Coding RNA SNHG Family as Promising Prognostic Biomarkers in Acute Myeloid Leukemia.
    Jian Shi, Weifeng Ding, Hong Lu.
      Background: Small nucleolar RNA host gene (SNHG) family members are newly recognized lncRNAs, which have been revealed to be oncogenes in several cancers. However, little studies investigated the expression and clinical implications of SNHGs in AML.Methods: Herein, we systemically determined the prognostic role of the expression of SNHG family members in acute myeloid leukemia (AML).
    Results: Among the expression of all SNHG family members, we identified that only SNHG7 and SNHG12 expression were found to have prognostic effects on overall survival (OS) and leukemia-free survival (LFS) in AML by Cox regression univariate analysis. Furthermore, Kaplan-Meier analysis showed that SNHG7 higher-expressed cases had markedly longer OS and LFS time than SNHG7 lower-expressed cases, whereas SNHG12 higher-expressed cases had markedly shorter OS and LFS time than SNHG12 lower-expressed cases. Interestingly, SNHG7 and SNHG12 expression were also associated with several prognosis-related clinical/molecular features such as white blood cell counts, FAB/cytogenetic classifications, IDH1 mutation, RUNX1 mutation, and NPM1 mutation. Despite the associations, Cox regression multivariate analysis confirmed the independent prognostic impact of SNHG7 and SNHG12 expression in AML. Notably, we further validated that both SNHG7 and SNHG12 expression was significantly increased in newly diagnosed AML patients.
    Conclusion: Our findings demonstrated that SNHG7 and SNHG12 expression act as independent prognostic indicators in AML.
    Keywords:  AML; LncRNA; SNHG; expression; prognosis
    DOI:  https://doi.org/10.2147/OTT.S265853
  9. J Clin Med. 2020 Sep 11. pii: E2934. [Epub ahead of print]9(9):
    Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence.
    Salihanur Darici, Hazem Alkhaldi, Gillian Horne, Heather G Jørgensen, Sandra Marmiroli, Xu Huang.
      Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.
    Keywords:  AML; LSC; PI3K/Akt; combination treatment strategy; drug resistance; mTOR; targeted therapy
    DOI:  https://doi.org/10.3390/jcm9092934
  10. Blood. 2020 Sep 14. pii: blood.2020007732. [Epub ahead of print]
    Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.
    Geoffrey L Uy, Ibrahim Aldoss, Matthew C Foster, Peter H Sayre, Matthew J Wieduwilt, Anjali S Advani, John E Godwin, Martha L Arellano, Kendra Sweet, Ashkan Emadi, Farhad Ravandi, Harry P Erba, Michael Byrne, Laura C Michaelis, Max S Topp, Norbert Vey, Fabio Ciceri, Matteo Giovanni Carrabba, Stefania Paolini, Gerwin Huls, Mojca Jongen-Lavrencic, Martin Wermke, Patrice Chevallier, Emmanuel Gyan, Christian Récher, Patrick Stiff, Kristen Pettit, Bob Löwenberg, Sarah Church, Erica Katherine Anderson, Jayakumar Vadakekolathu, Marianne T Santaguida, Michael P Rettig, John Muth, Teia Curtis, Erin Fehr, Kuo Guo, Jian Zhao, Ouiam Bakkacha, Kenneth Jacobs, Kathy Tran, Patrick Kaminker, Maya Kostova, Ezio Bonvini, Roland B Walter, Jan Kenneth Davidson-Moncada, Sergio Rutella, John F DiPersio.
      Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.
    DOI:  https://doi.org/10.1182/blood.2020007732
  11. Am J Hematol. 2020 Sep 17.
    The impact of cytogenetic risk on the outcomes of Allogeneic Hematopoietic Cell Transplantation in patients with relapsed/refractory acute myeloid leukemia: on behalf of the Acute Leukemia Working Party (ALWP) of the EBMT.
    Monica Poiani, Myriam Labopin, Giorgia Battipaglia, Dietrich W Beelen, Johanna Tischer, Jürgen Finke, Arne Brecht, Edouard Forcade, Arnold Ganser, Jakob R Passweg, Helene Labussiere-Wallet, Ibrahim Yakoub-Agha, Kerstin Schäfer-Eckart, Nicolaus Kroeger, Blandine Guffroy, Annalisa Ruggeri, Jordi Esteve, Arnon Nagler, Mohamad Mohty.
      Karyotypic analysis at time of diagnosis has an important value in determining initial response to treatment, remission duration and overall survival (OS) in acute myeloid leukemia (AML). Less is known about its value before allogeneic hematopoietic cell transplantation (allo-HCT) in patients transplanted with active disease, either relapsed or primary refractory (Rel-Ref) AML. We explored the impact of cytogenetic risk (stratification according to MRC-UK) in 2,089 patients with either Ref (n=972) or Rel AML (n=1117) transplanted during the period 2000-2017. Overall, 154 patients had a favorable risk, 1,283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Compared to the favorable risk group, intermediate and adverse risk patients were associated with worse leukemia-free survival and OS and also with a higher incidence of relapse. In a subgroup analysis of patients in the intermediate risk group harboring Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), this remained an important prognostic factor, being associated with worse outcomes. When analyzing patients according to the intensity of the conditioning regimen, no differences were observed for the main transplant outcomes. In conclusion, in patients diagnosed with AML and transplanted with active disease, karyotype remains an important prognostic factor, allowing splitting patients into different risk groups according to their cytogenetics. Similarly, FLT3-ITD mutation also remains a negative prognostic factor in this population. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26000
  12. Int J Med Sci. 2020 ;17(15): 2346-2356
    Conjugation of TLR7 Agonist Combined with Demethylation Treatment Improves Whole-Cell Tumor Vaccine Potency in Acute Myeloid Leukemia.
    Guocheng Zhong, Guangyi Jin, Wei Zeng, Changhua Yu, Yan Li, Ji Zhou, Li Zhang, Li Yu.
      Background: Acute myeloid leukemia (AML) is a malignant hematological disease with high refractory rate. Immune escape of AML cells is one of the underlying mechanisms mediating the relapse of the cancers. Various immunotherapies based on the 'patients' immune response to tumor cells have been developed to targeting the immune escape of AML cells, which lead to the minimal residual disease (MRD) after treatment. But the efficacy of those treatments or the combination of treatments remains unsatisfactory. Methods: A Toll-like receptor (TLR)-7 agonist SZU-106 was chemically synthesized. SZU-106 was conjugated to Decitabine (DAC), a demethylation agent, treated AML cells to construct tumor vaccine. The potency of the newly constructed AML cell vaccine, SZU-106-DAC-AML was tested in vitro and in vivo for the expression of tumor antigens and the activation level of immune responses. Results: Compared to the well characterized TLR7 agonist R848, SZU-106 has a comparable potency to activate TLR7 signaling pathway. SZU-106-DAC-AML, constructed by conjugating SZU-106 to DAC treated tumor cells, exhibited increased expression of tumor antigens, and enhanced the activation of DC cells and T cells in vitro and in vivo. The result of xenograft tumor model showed that SZU-106-DAC-AML tumor vaccine greatly inhibited tumor growth and prolonged animal survival. Conclusions: Conjugation of TLR7 agonist combined with up-regulation of tumor antigen expression improved the effectiveness of whole-cell tumor vaccine in AML.
    Keywords:  AML; SZU-106; TLR7; vaccine.
    DOI:  https://doi.org/10.7150/ijms.49983
  13. Clin Cancer Res. 2020 Sep 14. pii: clincanres.1600.2020. [Epub ahead of print]
    Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase 3, Randomized, Open-label, Multi-center FESTnd Study.
    Li Zhang, Li Meng, Bingcheng Liu, Yanli Zhang, Huanling Zhu, Jiuwei Cui, Aining Sun, Yu Hu, Jie Jin, Hao Jiang, Xi Zhang, Yan Li, Li Liu, Wanggang Zhang, Xiaoli Liu, Jian Gu, Jianhui Qiao, Guifang Ouyang, Xin Liu, Jianmin Luo, Ming Jiang, Xiaobao Xie, Jianyong Li, Chunting Zhao, Mei Zhang, Tonghua Yang, Jianxiang Wang.
      PURPOSE: Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP).EXPERIMENTAL DESIGN: In this study, 394 patients were randomized 1:1 to flumatinib 600 mg once daily (n=196) or imatinib 400 mg once daily (n=198).
    RESULTS: The rate of major molecular response (MMR) at 6 months (primary end point) was significantly higher with flumatinib than with imatinib (33.7% vs 18.3%, P=0.0006), as was the rate of MMR at 12 months (52.6% vs 39.6%, P=0.0102). At 3 months, the rate of early molecular response (EMR) was significantly higher in patients receiving flumatinib than in those receiving imatinib (82.1% vs 53.3%, P<0.0001). Compared with patients receiving imatinib, more patients receiving flumatinib achieved MR4 at 6, 9 and 12 months (8.7% vs 3.6%, P=0.0358; 16.8% vs 5.1%, P=0.0002; 23.0% vs 11.7%, P=0.0034, respectively). No patients had progression to accelerated phase or blast crisis in the flumatinib arm versus 4 patients in the imatinib arm by 12 months. Adverse events of edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia were more frequent in imatinib arm, whereas diarrhea and alanine transaminase elevation were more frequent in flumatinib arm.
    CONCLUSIONS: Patients receiving flumatinib achieved significantly higher rates of responses, faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1600
  14. Blood Adv. 2020 Sep 22. 4(18): 4417-4429
    Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.
    Claudia Tregnago, Ambra Da Ros, Elena Porcù, Maddalena Benetton, Manuela Simonato, Luca Simula, Giulia Borella, Katia Polato, Sonia Minuzzo, Giulia Borile, Paola Cogo, Silvia Campello, Alessandro Massi, Romeo Romagnoli, Barbara Buldini, Franco Locatelli, Martina Pigazzi.
      In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug's safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002001
  15. Oncol Rep. 2020 Aug 10.
    RAD52 aptamer regulates DNA damage repair and STAT3 in BRCA1/BRCA2‑deficient human acute myeloid leukemia.
    Yichuan Xu, Yansi Lin, Yuxuan Luo, Yanling Yang, Bing Long, Zhigang Fang, Lingling Liu, Jingwen Zhang, Xiangzhong Zhang.
      RAD52 (Radiation sensitive 52) is a key factor in DNA damage repair (DDR) bypass, which participates in single‑strand annealing (SSA) after DNA damage end excision, while breast cancer type 1 susceptibility protein (BRCA1)/breast cancer type 2 susceptibility protein (BRCA2) play critical roles in homologous recombination (HR) repair. The present study aimed to determine whether RAD52‑induced regulation of repair bypass occurs in acute myeloid leukemia (AML) cells and to explore the underlying mechanism. Herein, we applied an RAD52 aptamer to AML cells with downregulated BRCA1/2. RAD52 aptamer inhibited AML cell proliferation detected by cell counting, promoted cell apoptosis obtained by flow cytometry, and suppressed DNA damage repair behavior measured by comet assay and flow cytometry, after drug intervention during low expression of BRCA1/2. During this process, DDR‑related cell cycle checkpoint proteins were activated, and the cells were continuously arrested in the S/G2 phase, which affected the cell damage repair process. Concurrently, the expression levels of apoptosis‑related proteins were also altered. Furthermore, the expression of STAT3 and p‑STAT3 was downregulated by the RAD52 aptamer, suggesting that RAD52 affects the STAT3 signaling pathway. In summary, we present a possible role for RAD52 in DDR of BRCA1/2‑deficient AML cells that involves the STAT3 signaling pathway.
    DOI:  https://doi.org/10.3892/or.2020.7723
  16. Sci Adv. 2020 Aug;6(35): eaaz4551
    METTL6 is a tRNA m3C methyltransferase that regulates pluripotency and tumor cell growth.
    Valentina V Ignatova, Steffen Kaiser, Jessica Sook Yuin Ho, Xinyang Bing, Paul Stolz, Ying Xim Tan, Chee Leng Lee, Florence Pik Hoon Gay, Palma Rico Lastres, Raffaele Gerlini, Birgit Rathkolb, Antonio Aguilar-Pimentel, Adrián Sanz-Moreno, Tanja Klein-Rodewald, Julia Calzada-Wack, Emil Ibragimov, Magdalena Valenta, Saulius Lukauskas, Andrea Pavesi, Susan Marschall, Stefanie Leuchtenberger, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Sebastian Bultmann, Oliver J Rando, Ernesto Guccione, Stefanie M Kellner, Robert Schneider.
      Recently, covalent modifications of RNA, such as methylation, have emerged as key regulators of all aspects of RNA biology and have been implicated in numerous diseases, for instance, cancer. Here, we undertook a combination of in vitro and in vivo screens to test 78 potential methyltransferases for their roles in hepatocellular carcinoma (HCC) cell proliferation. We identified methyltransferase-like protein 6 (METTL6) as a crucial regulator of tumor cell growth. We show that METTL6 is a bona fide transfer RNA (tRNA) methyltransferase, catalyzing the formation of 3-methylcytidine at C32 of specific serine tRNA isoacceptors. Deletion of Mettl6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as impaired pluripotency. In mice, Mettl6 knockout results in reduced energy expenditure. We reveal a previously unknown pathway in the maintenance of translation efficiency with a role in maintaining stem cell self-renewal, as well as impacting tumor cell growth profoundly.
    DOI:  https://doi.org/10.1126/sciadv.aaz4551
  17. Target Oncol. 2020 Sep 17.
    Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia.
    Connie Kang, Hannah A Blair.
      Gilteritinib (Xospata®), a next-generation tyrosine kinase inhibitor (TKI), is approved in several countries/regions worldwide for the treatment of relapsed or refractory acute myeloid leukaemia (AML) in adults with FMS-like tyrosine kinase 3 (FLT3) mutations. In this patient population, oral gilteritinib significantly improved overall survival (OS) and the response rate for complete remission with full or partial haematological recovery compared with salvage chemotherapy in the phase III ADMIRAL trial. In an integrated safety analysis of patients with relapsed or refractory AML, the most commonly reported grade ≥ 3 treatment-related adverse events (AEs) in gilteritinib recipients included anaemia, febrile neutropenia and thrombocytopenia. Clinically relevant AEs of special interest (AESIs) with gilteritinib therapy included differentiation syndrome, posterior reversible encephalopathy syndrome, QT interval prolongation and pancreatitis. AEs, including AESIs, were generally manageable with dose reduction, interruption or discontinuation. All patients of reproductive potential should use contraception during gilteritinib treatment due to the risk of embryo-foetal toxicity. Given its convenient oral regimen, along with the poor prognosis and paucity of treatment options for adults with relapsed or refractory FLT3-mutated AML, gilteritinib represents a valuable first-line targeted monotherapy in these patients.
    DOI:  https://doi.org/10.1007/s11523-020-00749-3
  18. Cell Stem Cell. 2020 Sep 15. pii: S1934-5909(20)30400-8. [Epub ahead of print]
    Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development.
    Edie I Crosse, Sabrina Gordon-Keylock, Stanislav Rybtsov, Anahi Binagui-Casas, Hannah Felchle, Nneka C Nnadi, Kristina Kirschner, Tamir Chandra, Sara Tamagno, David J Webb, Fiona Rossi, Richard A Anderson, Alexander Medvinsky.
      Hematopoietic stem cells (HSCs) first emerge in the embryonic aorta-gonad-mesonephros (AGM) region. Studies of model organisms defined intersecting signaling pathways that converge to promote HSC emergence predominantly in the ventral domain of the dorsal aorta. Much less is known about mechanisms driving HSC development in humans. Here, to identify secreted signals underlying human HSC development, we combined spatial transcriptomics analysis of dorsoventral polarized signaling in the aorta with gene expression profiling of sorted cell populations and single cells. Our analysis revealed a subset of aortic endothelial cells with a downregulated arterial signature and a predicted lineage relationship with the emerging HSC/progenitor population. Analysis of the ventrally polarized molecular landscape identified endothelin 1 as an important secreted regulator of human HSC development. The obtained gene expression datasets will inform future studies on mechanisms of HSC development in vivo and on generation of clinically relevant HSCs in vitro.
    Keywords:  AGM region; HSC; embryo; endothelin; hematopoiesis; single cell transcriptome; spatial transcriptome
    DOI:  https://doi.org/10.1016/j.stem.2020.08.004
  19. Blood. 2020 Sep 14. pii: blood.2020007747. [Epub ahead of print]
    RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development.
    Tao Zhen, Yaqiang Cao, Gang Ren, Ling Zhao, R Katherine Hyde, Guadalupe Lopez, Dechun Feng, Lemlem Alemu, Keji Zhao, P Paul Liu.
      Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFβ-SMMHC mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11 induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f)with conditional Cbfb-MYH11 knockin mice (Cbfb+/56M). Upon Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb+/56Mmice developed leukemia in 5 months while no leukemia developed in Runx1f/fMx1-CreCbfb+/56Mmice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia initiating cell population induced by Cbfb-MYH11 in the bone marrow, decreased and disappeared in Runx1f/fMx1-CreCbfb+/56Mmice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage and leukemia initiation, were differentially expressed between Mx1-CreCbfb+/56Mand Runx1f/fMx1-CreCbfb+/56M mice. In addition, with chromatin immunocleavage sequencing (ChIC-seq) assay, we observed a significant enrichment of RUNX1/CBFβ-SMMHC target genes in Runx1f/fMx1-CreCbfb+/56M cells, especially among down-regulated genes, suggesting that RUNX1 and CBFβ-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbfb-MYH11 induced leukemogenesis by working together with CBFβ-SMMHC to regulate critical genes associated with the generation of a functional AMP population.
    DOI:  https://doi.org/10.1182/blood.2020007747
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