bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒08‒30
fifteen papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London


  1. Haematologica. 2020 Aug 27. pii: haematol.2020.249177. [Epub ahead of print]
    Hultmark S, Baudet A, Schmiderer L, Prabhala P, Palma-Tortosa S, Sandén C, Fioretos T, Sasidharan R, Larsson C, Lehmann S, Juliusson G, Ek F, Magnusson M.
      Combination treatment has proven effective for patients with acute promyelocytic leukemia, exemplifying the importance of therapy targeting multiple components of oncogenic regulation for a successful outcome. However, recent studies have shown that the mutational complexity of acute myeloid leukemia (AML) precludes the translation of molecular targeting into clinical success. Here as a complement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop personalized combinatorial treatments. First, we screened 513 natural compounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AMLs, while FLT3-ITD/mutations conferred resistance. The responding samples to H4, displayed increased expression of myeloid markers, a clear decrease in the nuclear-cytoplasmic ratio and the potential of re-activation of the monocytic transcriptional program reducing leukemia propagation in vivo. By combinatorial screening using H4 and molecules with defined targets, we demonstrated that H4 induces differentiation by the activation of protein kinase C (PKC) signaling pathway, and in line with this, activates PKC phosphorylation and translocation of PKC to the cell membrane. Furthermore, the combinatorial screening identified a bromo- and extra-terminal domain (BET) inhibitor that could further improve H4-dependent leukemic differentiation in FLT3 wild-type monocytic AML. Taken together, this illustrates the value of an unbiased and multiplex screening platform for developing combinatorial therapeutic approaches for AML.
    Keywords:  Acute Myeloid Leukemia; Acute monocytic leukemia; Combination therapy; Differentiation therapy; Small molecule screening
    DOI:  https://doi.org/10.3324/haematol.2020.249177
  2. Blood Cancer J. 2020 Aug 25. 10(8): 85
    Travaglini S, Angelini DF, Alfonso V, Guerrera G, Lavorgna S, Divona M, Nardozza AM, Consalvo MI, Fabiani E, De Bardi M, Neri B, Forghieri F, Marchesi F, Paterno G, Cerretti R, Barragan E, Fiori V, Dominici S, Del Principe MI, Venditti A, Battistini L, Arcese W, Lo-Coco F, Voso MT, Ottone T.
      Acute myeloid leukemia (AML) with FLT3-ITD mutations (FLT3-ITDmut) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts for FLT3-ITD-positivity. The aim of this study was to characterize the distribution of FLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture of FLT3-ITDmut AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients with FLT3-ITDmut AML (n = 12). A higher FLT3-ITDmut load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/-,CD25-,CD99low/-) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higher FLT3-ITDmut burden was also observed in LPCs of AML patients with a small FLT3-ITDmut clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows that FLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target in FLT3-ITDmut AML.
    DOI:  https://doi.org/10.1038/s41408-020-00352-9
  3. Haematologica. 2020 Aug 27. pii: haematol.2020.252825. [Epub ahead of print]
    Caprioli C, Lussana F, Salmoiraghi S, Cavagna R, Buklijas K, Elidi L, Zanghi' P, Michelato A, Delaini F, Oldani E, Intermesoli T, Grassi A, Gianfaldoni G, Mannelli F, Ferrero D, Audisio E, Terruzzi E, De Paoli L, Cattaneo C, Borlenghi E, Cavattoni I, Tajana M, Scattolin AM, Mattei D, Corradini P, Campiotti L, Ciceri F, Bernardi M, Todisco E, Cortelezzi A, Falini B, Pavoni C, Bassan R, Spinelli O, Rambaldi A.
      Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).
    Keywords:  Acute Myeloid Leukemia; Cytogenetics and Molecular Genetics; Myelodysplastic Syndromes
    DOI:  https://doi.org/10.3324/haematol.2020.252825
  4. Cancers (Basel). 2020 Aug 26. pii: E2427. [Epub ahead of print]12(9):
    Testa U, Castelli G, Pelosi E.
      Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.
    Keywords:  gene mutations; isocitrate dehydrogenase; leukemia; targeted therapy
    DOI:  https://doi.org/10.3390/cancers12092427
  5. Nat Cancer. 2020 Mar;1(3): 345-358
    Tran TQ, Hanse EA, Habowski AN, Li H, Gabra MBI, Yang Y, Lowman XH, Ooi AM, Liao SY, Edwards RA, Waterman ML, Kong M.
      Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
    Keywords:  Wnt signaling; cancer metabolism; colon cancer; epigenetics; glutamine
    DOI:  https://doi.org/10.1038/s43018-020-0035-5
  6. J Mater Chem B. 2020 Aug 26.
    Kaundal B, Kushwaha AC, Srivastava AK, Karmakar S, Choudhury SR.
      Acute myeloid leukemia (AML), which is common in the elderly population, accounts for poor long-term survival with a high possibility of relapse. The associated lack of currently developed therapeutics is directing the search for new therapeutic targets relating to AML. EZH2 (Enhancer of Zeste Homolog 2) is a histone methyltransferase member of the polycomb-group (PcG) family, and its significant overexpression in AML means it has emerged as a potential epigenetic target. Here, we propose the human serum albumin (HSA) nanoparticle based delivery of small interfering RNA (siRNA), which can target EZH2-expressing genes in AML. EZH2 specific siRNA loaded in a polyethyleneimine (PEI) conjugated HSA nanocarrier can overcome the systemic instability of siRNA and precisely target the AML cell population for increased EZH2 gene silencing. A stable nanosized complex (HSANPs-PEI@EZH2siRNA), achieved via the electrostatic interaction of PEI and EZH2 siRNA, shows increased systemic stability and hemocompatibility, and enhanced EZH2 gene silencing activity in vitro, compared to conventional transfection reagents. HSANPs-PEI@EZH2siRNA-treated AML cells showed downregulated EZH2, which is associated with a reduced level of Bmi-1 protein, and H3K27me3 and H2AK119ub modification. The ubiquitin-mediated proteasomal degradation pathway plays a critical role in the downregulation of associated proteins following HSANPs-PEI@EZH2siRNA exposure to AML cells. c-Myb is the AML-responsive transcription factor that directly binds on the EZH2 promoter and was downregulated in HSANPs-PEI@EZH2siRNA-treated AML cells. The systemic exposure to HSANPs-PEI@EZH2siRNA of AML engrafted immunodeficient nude mice displayed efficient EZH2 gene silencing and a reduced AML cell population in peripheral blood and bone marrow. The present study demonstrates a non-viral siRNA delivery system for epigenetic targeting based superior anti-leukemic therapy.
    DOI:  https://doi.org/10.1039/d0tb01177k
  7. BMC Res Notes. 2020 Aug 26. 13(1): 394
    Tran VT, Phan TT, Mac HP, Tran TT, Ho TT, Pho SP, Nguyen VN, Vo TM, Nguyen HT, Le TT, Vo TH, Nguyen ST.
      OBJECTIVE: The same immuno-phenotype between HLA-DR-negative acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) causes APL rapid screening to become difficult. This study aimed to identify the associated antigens for APL and the best model in clinical uses.RESULTS: A total of 36 APL (PML-RARA+) and 29 HLA-DR-negative non-APL patients enrolled in this study. When a cut-off point of 20% events was applied to define positive or negative status, APL and non-APL patients share a similar immuno-phenotype of CD117, CD34, CD11b, CD13, CD33, and MPO (P > 0.05). However, expression intensity of CD117 (P = 0.002), CD13 (P < 0.001), CD35 (P < 0.001), CD64 (P < 0.001), and MPO (P < 0.001) in APL are significantly higher while CD56 (P = 0.049) is lower than in non-APL subjects. The Bayesian Model Averaging (BMA) analysis identified CD117 (≥ 49% events), CD13 (≥ 88% events), CD56 (≤ 25% events), CD64 (≥ 42% events), and MPO (≥ 97% events) antigens as an optimal model for APL diagnosis. A combination of these factors resulted in an area under curve (AUC) value of 0.98 together with 91.7% sensitivity and 93.1% specificity, which is better than individual markers (AUC were 0.76, 0.84, 0.65, 0.82, and 0.85, respectively) (P = 0.001).
    Keywords:  APL; CD117; CD13; CD56; CD64; MPO; PML–RARA
    DOI:  https://doi.org/10.1186/s13104-020-05235-7
  8. Cell. 2020 Aug 20. pii: S0092-8674(20)30991-0. [Epub ahead of print]
    Zhang JZ, Lu TW, Stolerman LM, Tenner B, Yang JR, Zhang JF, Falcke M, Rangamani P, Taylor SS, Mehta S, Zhang J.
      The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIα LLPS and induces aberrant cAMP signaling. Loss of RIα LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.
    Keywords:  DnaJB1-PKA; FLC; FRET; biosensor; fibrolamellar carcinoma; live cell imaging; membraneless organelle; signal transduction; split GFP
    DOI:  https://doi.org/10.1016/j.cell.2020.07.043
  9. Epigenetics. 2020 Aug 28. 1-10
    DiNardo CD, Beird HC, Estecio M, Hardikar S, Takahashi K, Bannon SA, Borthakur G, Jabbour E, Gumbs C, Khoury JD, Routbort M, Gong T, Kondo K, Kantarjian H, Garcia-Manero G, Chen T, Futreal PA.
      Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.
    Keywords:  AML; DNMT3A; germline; hereditary; predisposition
    DOI:  https://doi.org/10.1080/15592294.2020.1809871
  10. N Engl J Med. 2020 08 27. 383(9): 813-824
    Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC, Peled N, Weiss J, Kim YJ, Ohe Y, Nishio M, Park K, Patel J, Seto T, Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, Falchook G, Ebata K, Nguyen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg SM, Goto K, Subbiah V.
      BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.
    RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.
    CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
    DOI:  https://doi.org/10.1056/NEJMoa2005653
  11. J Clin Invest. 2020 Aug 24. pii: 137723. [Epub ahead of print]
    Biernacki MA, Foster KA, Woodward KB, Coon ME, Cummings C, Cunningham TM, Dossa RG, Brault M, Stokke J, Olsen TM, Gardner K, Estey E, Meshinchi S, Rongvaux A, Bleakley M.
      Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01+ donors. High-avidity CD8+ T cell clones isolated from healthy donors killed CBFB-MYH11+ HLA-B*40:01+ AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11+ HLA-B*40:01+ AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into CD8+ T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.
    Keywords:  Cancer immunotherapy; Immunology; Leukemias; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI137723
  12. Int J Lab Hematol. 2020 Aug 27.
    El-Gamal RAE, Hashem AE, Habashy DM, Abou Elwafa MAZ, Boshnak NH.
      INTRODUCTION: Nucleophosmin 1 (NPM1) mutation is one of the most frequent gene mutations in adult acute myeloid leukemia (AML), being detected in 35% of all cases and in up to 60% of patients with normal karyotype AML. AML with mutated NPM1 has distinct pathology, immunophenotyping, and confirmed favorable prognostic significance. Hence, AML with mutated NPM1 is a separate entity in the revised 2016 World Health Organization classification. This study aimed to evaluate the use of a reproducible flow cytometry approach in the assay of mutant NPM1 protein in AML patients and to correlate flow cytometric results with the NPM1 gene mutation.METHODS: Eighty-nine newly diagnosed AML patients were evaluated for the expression of mutant NPM1 using flow cytometry and for the presence of NPM1 exon 12 mutations using high-resolution melting polymerase chain reaction (HRM PCR).
    RESULTS: The NPM1 mutation was found in 35 (39.3%) patients by HRM PCR. These patients showed a significantly higher level of percentage of positive-stained cells (% positive cells) and normalized median fluorescence intensity (MFI) for mutant NPM1 by flow cytometry than the negative mutation group.
    CONCLUSION: Flow cytometric detection of mutant NPM1 offers a possible tool to indicate NPM1 mutational status.
    Keywords:  HRM PCR; NPM1; acute myeloid leukemia; flow cytometry
    DOI:  https://doi.org/10.1111/ijlh.13317
  13. Am J Hematol. 2020 Aug 24.
    Morsia E, McCullough K, Joshi M, Cook J, Alkhateeb HB, Al-Kali A, Begna K, Elliott M, Hogan W, Litzow M, Shah M, Pardanani A, Patnaik M, Tefferi A, Gangat N.
      Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n=27) were studied. CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (p=0.005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (p=0.31). Moreover, CEPBA mutations (p=0.03) and neutropenia (p=0.05) emerged as predictors of complete response. Survival was prolonged in patients achieving CR/CRi (17 months vs 3 months without CR/CRi, p=0.0009); conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥ 2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 months vs 3 months with/without CR/CRi; p=0.0003), and TP53 mutation status (p=0.04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.25978
  14. Cancers (Basel). 2020 Aug 24. pii: E2400. [Epub ahead of print]12(9):
    Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, Su Y, Carter J, Li X, Polin L, Kushner J, Dzinic SH, White K, Wang G, Taub JW, Ge Y.
      Targeting oxidative phosphorylation (OXPHOS) is a promising strategy to improve treatment outcomes of acute myeloid leukemia (AML) patients. IACS-010759 is a mitochondrial complex I inhibitor that has demonstrated preclinical antileukemic activity and is being tested in Phase I clinical trials. However, complex I deficiency has been reported to inhibit apoptotic cell death through prevention of cytochrome c release. Thus, combining IACS-010759 with a BH3 mimetic may overcome this mechanism of resistance leading to synergistic antileukemic activity against AML. In this study, we show that IACS-010759 and venetoclax synergistically induce apoptosis in OXPHOS-reliant AML cell lines and primary patient samples and cooperatively target leukemia progenitor cells. In a relatively OXPHOS-reliant AML cell line derived xenograft mouse model, IACS-010759 treatment significantly prolonged survival, which was further enhanced by treatment with IACS-010759 in combination with venetoclax. Consistent with our hypothesis, IACS-010759 treatment indeed retained cytochrome c in mitochondria, which was completely abolished by venetoclax, resulting in Bak/Bax- and caspase-dependent apoptosis. Our preclinical data provide a rationale for further development of the combination of IACS-010759 and venetoclax for the treatment of patients with AML.
    Keywords:  Bcl-2; IACS-010759; acute myeloid leukemia; oxidative phosphorylation; venetoclax
    DOI:  https://doi.org/10.3390/cancers12092400
  15. Sci Rep. 2020 Aug 24. 10(1): 13722
    Kosik P, Durdik M, Jakl L, Skorvaga M, Markova E, Vesela G, Vokalova L, Kolariková L, Horvathova E, Kozics K, Belyaev I.
      There is clear evidence that ionizing radiation (IR) causes leukemia. For many types of leukemia, the preleukemic fusion genes (PFG), as consequences of DNA damage and chromosomal translocations, occur in hematopoietic stem and progenitor cells (HSPC) in utero and could be detected in umbilical cord blood (UCB) of newborns. However, relatively limited information is available about radiation-induced apoptosis, DNA damage and PFG formation in human HSPC. In this study we revealed that CD34+ HSPC compared to lymphocytes: (i) are extremely radio-resistant showing delayed time kinetics of apoptosis, (ii) accumulate lower level of endogenous DNA damage/early apoptotic γH2AX pan-stained cells, (iii) have higher level of radiation-induced 53BP1 and γH2AX/53BP1 co-localized DNA double stranded breaks, and (iv) after low dose of IR may form very low level of BCR-ABL PFG. Within CD34+ HSPC we identified CD34+CD38+ progenitor cells as a highly apoptosis-resistant population, while CD34+CD38- hematopoietic stem/multipotent progenitor cells (HSC/MPP) as a population very sensitive to radiation-induced apoptosis. Our study provides critical insights into how human HSPC respond to IR in the context of DNA damage, apoptosis and PFG.
    DOI:  https://doi.org/10.1038/s41598-020-70657-z