bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020–10–25
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.
  2. Therapeutic effect of TRC105 and decitabine combination in AML xenografts.
  3. Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia.
  4. FLT3 ligand in acute myeloid leukemia: a simple test with deep implications.
  5. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics.
  6. A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells.
  7. Delineation of target expression profiles in CD34+/CD38- and CD34+/CD38+ stem and progenitor cells in AML and CML.
  8. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia.
  9. MicroRNA-143 sensitizes acute myeloid leukemia cells to cytarabine via targeting ATG7- and ATG2B-dependent autophagy.
  10. Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by pro-inflammatory cytokine induced lncRNA Morrbid.
  11. Differential sensitivity of acute myeloid leukemia cells to daunorubicin depends on P2X7A versus P2X7B receptor expression.
  12. CLEC12A and CD33 co-expression as preferential target on pediatric AML for combinatorial immunotherapy.
  13. Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia.
  14. Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML.
  15. The LSD1 Inhibitor Iadademstat Is Active in Acute Myeloid Leukemia.
  16. AMPK activation primes cytoplasmic translocation and autophagic degradation of the BCR-ABL protein in CML cells.
  17. Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach.
  18. JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML.
  19. Concomitant Administration of Direct Oral Anticoagulants in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors.
  20. MCART1/SLC25A51 is required for mitochondrial NAD transport.
  21. Evolving treatment patterns and outcomes in older patients (≥60 years) with AML: changing everything to change nothing?
  22. Hematopoietic Stem Cell Renewal Drives Myeloproliferative Neoplasms.
  23. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.
  24. Terminal deoxynucleotidyl transferase (TdT) expression is associated with FLT3-ITD mutations in Acute Myeloid Leukemia.
  25. Rerouting DOT1L inhibitors in leukemia.
  26. Comprehensive in-silico analysis of damage associated SNPs in hOCT1 affecting Imatinib response in chronic myeloid leukemia.
  27. Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome.
  1. Blood Adv. 2020 Oct 27. 4(20): 5062-5077
    Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.
    Emma Morrish, Anthony Copeland, Donia M Moujalled, Jason A Powell, Natasha Silke, Ann Lin, Kate E Jarman, Jarrod J Sandow, Gregor Ebert, Liana Mackiewicz, Jessica A Beach, Elizabeth L Christie, Alexander C Lewis, Giovanna Pomilio, Karla C Fischer, Laura MacPherson, David D L Bowtell, Andrew I Webb, Marc Pellegrini, Mark A Dawson, Stuart M Pitson, Andrew H Wei, John Silke, Gabriela Brumatti.
      The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001576
  2. Heliyon. 2020 Oct;6(10): e05242
    Therapeutic effect of TRC105 and decitabine combination in AML xenografts.
    June Baik, Martin Felices, Ashley Yingst, Charles P Theuer, Michael R Verneris, Jeffrey S Miller, Rita Perlingeiro.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105+ AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients.
    Keywords:  AML; Antibody; Cancer research; Cell biology; Chemotherapy; Decitabine; Hematology; Molecular biology; TRC105; Xenografts
    DOI:  https://doi.org/10.1016/j.heliyon.2020.e05242
  3. Sci Rep. 2020 Oct 19. 10(1): 17695
    Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia.
    G D Bailey, L Doolan, A Baskar, L C Smith, C H Seedhouse.
      Nucleophosmin is commonly both over-expressed and mutated in acute myeloid leukemia (AML). NPM1 mutations are always heterozygous. In addition, NPM1 has a number of different splice variants with the major variant encoded by exons 1-9 and 11-12 (NPM1.1). Further variants include NPM1.2 which lacks exons 8 and 10 and NPM1.3 which comprises exons 1-10 (and so lacks the region of sequence mutated in AML). In this study we quantified the expression of these three variants in 108 AML patient samples with and without NPM1 mutations and also assessed the level of expression from the wild-type and mutant alleles in variants NPM1.1 and NPM1.2. The results show that NPM1.1 is the most commonly expressed variant, however transcripts from wild-type and mutated alleles do not occur at equal levels, with a significant bias toward the mutated allele. Considering the involvement of mutant nucleophosmin in the progression and maintenance of AML, a bias towards mutated transcripts could have a significant impact on disease maintenance.
    DOI:  https://doi.org/10.1038/s41598-020-73782-x
  4. Leuk Lymphoma. 2020 Oct 20. 1-7
    FLT3 ligand in acute myeloid leukemia: a simple test with deep implications.
    Pierre Peterlin, Patrice Chevallier, Steven Knapper, Matthew Collin.
      In contrast to Fms-like tyrosine kinase 3 (FLT3), the influence of FLT3 ligand (FLT3L) on acute myeloid leukemia (AML) biology and disease prognosis has been poorly described. Here we provide an overview of the role played by FLT3L in AML. While being a cytokine implicated in the regulation of hematopoiesis, both in normal situation and after intensive chemotherapy, FLT3L has also a role in enhancing proliferation, inhibiting apoptosis and conferring resistance to FLT3 inhibitors in AML. Moreover, recent independent data show how its measurement may be helpful in the disease management. Indeed, FLT3L could provide a low cost, rapid and noninvasive assessment of chemosensitivity and blast clearance that has robust prognostic significance for patients with AML.
    Keywords:  FLT3 ligand; acute myeloid leukemia; cytokine and chemokine biology; cytokine production and paraneoplastic conditions; prognostication
    DOI:  https://doi.org/10.1080/10428194.2020.1834091
  5. Nat Commun. 2020 10 21. 11(1): 5327
    Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics.
    Kiyomi Morita, Feng Wang, Katharina Jahn, Tianyuan Hu, Tomoyuki Tanaka, Yuya Sasaki, Jack Kuipers, Sanam Loghavi, Sa A Wang, Yuanqing Yan, Ken Furudate, Jairo Matthews, Latasha Little, Curtis Gumbs, Jianhua Zhang, Xingzhi Song, Erika Thompson, Keyur P Patel, Carlos E Bueso-Ramos, Courtney D DiNardo, Farhad Ravandi, Elias Jabbour, Michael Andreeff, Jorge Cortes, Kapil Bhalla, Guillermo Garcia-Manero, Hagop Kantarjian, Marina Konopleva, Daisuke Nakada, Nicholas Navin, Niko Beerenwinkel, P Andrew Futreal, Koichi Takahashi.
      Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.
    DOI:  https://doi.org/10.1038/s41467-020-19119-8
  6. Leukemia. 2020 Oct 23.
    A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells.
    Upasana Sunil Arvindam, Paulien M M van Hauten, Dawn Schirm, Nicolaas Schaap, Willemijn Hobo, Bruce R Blazar, Daniel A Vallera, Harry Dolstra, Martin Felices, Jeffrey S Miller.
      The low 5-year survival rate for patients with acute myeloid leukemia (AML), primarily caused due to disease relapse, emphasizes the need for better therapeutic strategies. Disease relapse is facilitated by leukemic stem cells (LSCs) that are resistant to standard chemotherapy and promote tumor growth. To target AML blasts and LSCs using natural killer (NK) cells, we have developed a trispecific killer engager (TriKETM) molecule containing a humanized anti-CD16 heavy chain camelid single-domain antibody (sdAb) that activates NK cells, an IL-15 molecule that drives NK-cell priming, expansion and survival, and a single-chain variable fragment (scFv) against human CLEC12A (CLEC12A TriKE). CLEC12A is a myeloid lineage antigen that is highly expressed by AML cells and LSCs, but not expressed by normal hematopoietic stem cells (HSCs), thus minimizing off-target toxicity. The CLEC12A TriKE induced robust NK-cell specific proliferation, enhanced NK-cell activation, and killing of both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Additionally, the CLEC12A TriKE was able to reduce tumor burden in preclinical mouse models. These findings highlight the clinical potential of the CLEC12A TriKE for the effective treatment of AML.
    DOI:  https://doi.org/10.1038/s41375-020-01065-5
  7. Blood Adv. 2020 Oct 27. 4(20): 5118-5132
    Delineation of target expression profiles in CD34+/CD38- and CD34+/CD38+ stem and progenitor cells in AML and CML.
    Harald Herrmann, Irina Sadovnik, Gregor Eisenwort, Thomas Rülicke, Katharina Blatt, Susanne Herndlhofer, Michael Willmann, Gabriele Stefanzl, Sigrid Baumgartner, Georg Greiner, Axel Schulenburg, Niklas Mueller, Werner Rabitsch, Martin Bilban, Gregor Hoermann, Berthold Streubel, Daniel A Vallera, Wolfgang R Sperr, Peter Valent.
      In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n = 274) or CML (n = 97) and controls (n = 288) for expression of cell membrane antigens on CD34+/CD38- and CD34+/CD38+ cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD34+/CD38- and CD34+/CD38+ cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD34+/CD38- LSCs exhibited an almost invariable aberration profile, defined as CD25+/CD26+/CD56+/CD93+/IL-1RAP+. By contrast, in patients with AML, CD34+/CD38- cells variably expressed "aberrant" membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication-mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD34+/CD38- LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001742
  8. J Hematol Oncol. 2020 Oct 19. 13(1): 139
    Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia.
    Lindsey T Brinton, Pu Zhang, Katie Williams, Daniel Canfield, Shelley Orwick, Steven Sher, Ronni Wasmuth, Larry Beaver, Casey Cempre, Jordan Skinner, Matthew Cannon, Mukul Govande, Bonnie Harrington, Amy Lehman, John C Byrd, Rosa Lapalombella, James S Blachly.
      Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
    Keywords:  Acute myeloid leukemia; BCL2; Combination therapy; FLT3; Gilteritinib; Midostaurin; Synergy; Venetoclax
    DOI:  https://doi.org/10.1186/s13045-020-00973-4
  9. Aging (Albany NY). 2020 Oct 19. 12
    MicroRNA-143 sensitizes acute myeloid leukemia cells to cytarabine via targeting ATG7- and ATG2B-dependent autophagy.
    Hao Zhang, Jianmin Kang, Ling Liu, Lulu Chen, Saisai Ren, Yanling Tao.
      Targeting autophagy holds promise to enhance chemosensitivity in acute myeloid leukemia (AML). MicroRNA-143 (miR-143) has been found to suppress autophagy, however, it is not clear whether miR-143 augments cytarabine cytotoxicity in AML. Here, we report that cytarabine treatment reduces miR-143 expression in AML cell lines and primary AML cells. Moreover, ectopic expression of miR-143 further decreases cell viability in cytarabine-treated AML cells. By contrast, miR-143 knockdown inhibits cytarabine-induced cytotoxicity, together indicating a role of miR-143 in enhancing cytarabine sensitivity in AML. Subsequently, we show that miR-143 inhibits autophagy in cytarabine-treated AML cells by directly targeting autophagy-related proteins (ATG), ATG7 and ATG2B, two critical known components of autophagic machinery. More importantly, autophagy reconstructed via co-expression of ATG7 and ATG2B substantially attenuates miR-143-enhanced cytotoxicity, which is associated with suppression of caspase-dependent apoptotic pathway. Overall, this study demonstrates that targeting ATG7 and ATG2B-dependent autophagy is a critical mechanism by which miR-143 sensitizes AML to cytarabine, implicating it as a potential therapeutic target in AML treatment.
    Keywords:  ATG7; acute myeloid leukemia; autophagy; cytarabine; microRNA-143
    DOI:  https://doi.org/10.18632/aging.103614
  10. J Clin Invest. 2020 Oct 22. pii: 140707. [Epub ahead of print]
    Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by pro-inflammatory cytokine induced lncRNA Morrbid.
    Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth P Nephew, Jonathan J Kotzin, Adam Williams, Jorge Henao-Mejia, Laura S Haneline, Reuben Kapur.
      Diabetes mellitus (DM) is a risk factor for cancer development. However, the role of DM induced hyperglycemic stress (HG) in the development of blood cancer is poorly understood, largely due to lack of appropriate animal models. Epidemiologic studies show that individuals with DM are more likely to possess higher rate of mutations in genes found in pre-leukemic stem and progenitor cells (pre-LHSC/Ps) including in the epigenetic regulator TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Cell intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the role of extrinsic factors is poorly understood. Utilizing a novel mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces HG and Type-1 DM, we show that the compound mutant mice develop a lethal form of MPN and/or acute myeloid leukemia (AML). RNAseq revealed that this is in part due to upregulation of pro-inflammatory pathways, thereby generating a feedforward loop, including the expression of an anti-apoptotic lncRNA Morrbid. Loss of Morrbid in the compound mutants rescues the lethality and mitigates the development of MPN/AML. Our results describe a novel mouse model for age-dependent AML/MPN and suggest that HG stress acts as an environmental driver for myeloid neoplasm, which could be effectively prevented by reducing the expression of inflammation-related lncRNA Morrbid.
    Keywords:  Diabetes; Hematology; Inflammation; Leukemias
    DOI:  https://doi.org/10.1172/JCI140707
  11. Cell Death Dis. 2020 Oct 18. 11(10): 876
    Differential sensitivity of acute myeloid leukemia cells to daunorubicin depends on P2X7A versus P2X7B receptor expression.
    Anna Pegoraro, Elisa Orioli, Elena De Marchi, Valentina Salvestrini, Asia Milani, Francesco Di Virgilio, Antonio Curti, Elena Adinolfi.
      Acute myeloid leukemia (AML) is a common adult leukemia often arising from a preexistent myelodysplastic syndrome (MDS). High mortality rates of AML are caused by relapse and chemoresistance; therefore, we analyzed the role of P2X7 receptor (P2X7R) splice variants A and B in AML progression and response to chemotherapy. The expression of P2X7RA and P2X7RB was investigated in samples obtained from MDS and AML untreated subjects or AML patients in relapse or remission after chemotherapy. Both P2X7RA and P2X7RB were overexpressed in AML versus MDS suggesting a disease-promoting function. However, in relapsing patients, P2X7RA was downmodulated, while P2X7RB was upmodulated. Treatment with daunorubicin (DNR), one of the main chemotherapeutics for AML, upregulated P2X7RB expression while reducing P2X7RA mRNA in AML blasts. Interestingly, DNR administration also caused ATP release from AML blasts suggesting that, following chemotherapy, activation of the receptor isoforms via their agonist will be responsible for the differential survival of blasts overexpressing P2X7RA versus P2X7RB. Indeed, AML blasts expressing high levels of P2X7RA were more prone to cell death if exposed to DNR, while those overexpressing P2X7RB were more vital and even protected against DNR toxicity. These data were reproducible also in HEK-293 cells separately expressing P2X7RA and B. P2X7RA facilitation of DNR toxicity was in part due to increased uptake of the drug inside the cell that was lost upon P2X7RB expression. Finally, in an AML xenograft model administration of DNR or the P2X7R antagonist, AZ10606120 significantly reduced leukemic growth and coadministration of the drugs proved more efficacious than single treatment as it reduced both P2X7RA and P2X7RB levels and downmodulated c-myc oncogene. Taken together, our data suggest P2X7RA and P2X7RB as potential prognostic markers for AML and P2X7RB as a therapeutic target to overcome chemoresistance in AML relapsing patients.
    DOI:  https://doi.org/10.1038/s41419-020-03058-9
  12. Blood. 2020 Oct 22. pii: blood.2020006921. [Epub ahead of print]
    CLEC12A and CD33 co-expression as preferential target on pediatric AML for combinatorial immunotherapy.
    Semjon Willier, Paula Rothämel, Maximilian Hastreiter, Jonas Wilhelm, Dana Stenger, Franziska Blaeschke, Meino Rohlfs, Theresa Kaeuferle, Irene Schmid, Michael H Albert, Vera Binder, Marion Subklewe, Christoph Klein, Tobias Feuchtinger.
      Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting and several suitable immunotargets (HAVCR2/CD33 or HAVCR2/CLEC12A) were identified in adult AML. However, clinical and biologic characteristics differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA-sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principle component analysis. Immunotargets known from adult AML such as IL3RA were not overexpressed in pediatric AML compared to healthy precursors by RNA-sequencing. CD33 and CLEC12A were the most upregulated immunotargets on RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A mutated infant AML cluster separately by RNA-sequencing, overexpress FLT3 and hence CD33/FLT3 co-targeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSC) and both are restricted to healthy hematopoietic tissue, while CD33 and FLT3 is expressed on HSC. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A/CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33/FLT3 as immunotargets specific for KMT2A mutated infant AML.
    DOI:  https://doi.org/10.1182/blood.2020006921
  13. Oncogenesis. 2020 Oct 22. 9(10): 94
    Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia.
    Godelieve Meunier, Rudy Birsen, Clarisse Cazelles, Maya Belhadj, Lilia Cantero-Aguilar, Olivier Kosmider, Michaela Fontenay, Nabih Azar, Patrick Mayeux, Nicolas Chapuis, Jerôme Tamburini, Didier Bouscary.
      Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and L-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41389-020-00278-8
  14. Blood Adv. 2020 Oct 27. 4(20): 5040-5049
    Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML.
    Giuseppe Visani, Federica Loscocco, Mike Dennis, Eliana Zuffa, Anna Candoni, Alberto Sensi, Barbara Giannini, Gerardo Musuraca, Anna Maria Mianulli, Marino Clavio, Marco Rocchi, Davide Gibellini, Mohsen Navari, Amanda Gilkes, Pier Paolo Piccaluga, Alessandro Isidori.
      Tosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acute myeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120 mg tosedostat orally once daily combined with subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Induction mortality was 12%. According to an intention-to-treat analysis, the complete remission (CR) rate was 48.5%, and thus the primary end point of the study was reached (expected CR, 25%). The partial remission rate was 6.1%, with an overall response rate of 54.5%. Furthermore, 4 of 33 patients had stable disease (median: 286 days). The median progression-free survival and overall survival (OS) were 203 days and 222 days, respectively. Responding patients had a longer median OS than nonresponding patients (P = .001). A microarray analysis performed in 29 of 33 patients identified 188 genes associated with clinical response (CR vs no CR). Three of them (CD93, GORASP1, CXCL16) were validated by quantitative polymerase chain reaction, which correctly classified 83% of the patients. Specifically, CR achievement was efficiently predicted by the gene expression patterns, with an overall accuracy exceeding 90%. Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML. This trial has been registered at the European Medicines Agency and on the European Clinical Trials Database (https://www.clinicaltrialsregister.eu) as #2012-000334-19.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002305
  15. Cancer Discov. 2020 Oct 23.
    The LSD1 Inhibitor Iadademstat Is Active in Acute Myeloid Leukemia.
      In a phase I trial, iadademstat induced blast differentiation and reduced bone marrow blast burden.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-155
  16. Cancer Sci. 2020 Oct 18.
    AMPK activation primes cytoplasmic translocation and autophagic degradation of the BCR-ABL protein in CML cells.
    Daisuke Koyama, Jiro Kikuchi, Yoshiaki Kuroda, Masatsugu Ohta, Yusuke Furukawa.
      Chronic myeloid leukemia (CML) is driven by the BCR-ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells especially when the disease is in advanced stages. The BCR-ABL protein activates AMP-activated protein kinase (AMPK) for ATP production and the mechanistic target of rapamycin (mTOR) pathway to suppress autophagy. BCR-ABL is detected in the nuclei of advanced-stage CML cells, in which ATP is sufficiently supplied via enhanced glucose metabolism. AMPK is further activated under energy-deprived conditions and triggers autophagy via ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14-3-3 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR-ABL in a BCR-ABL/14-3-3τ/Beclin1/XPO1 complex. Cytoplasmic BCR-ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that may be useful for treating TKI-resistant CML.
    Keywords:  AMPK; BCR-ABL; autophagy; cancer metabolism; mTOR
    DOI:  https://doi.org/10.1111/cas.14698
  17. Pediatr Res. 2020 Oct 17.
    Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach.
    Barbara Depreter, Barbara De Moerloose, Karl Vandepoele, Anne Uyttebroeck, An Van Damme, Eva Terras, Barbara Denys, Laurence Dedeken, Marie-Françoise Dresse, Jutte Van der Werff Ten Bosch, Mattias Hofmans, Jan Philippé, Tim Lammens.
       BACKGROUND: Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers.
    METHODS: Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis.
    RESULTS: Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast.
    CONCLUSION: Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML.
    IMPACT: Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls.Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis.These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy.Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
    DOI:  https://doi.org/10.1038/s41390-020-01199-3
  18. J Exp Med. 2021 Feb 01. pii: e20201268. [Epub ahead of print]218(2):
    JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML.
    Tracy Dagher, Nabih Maslah, Valérie Edmond, Bruno Cassinat, William Vainchenker, Stéphane Giraudier, Florence Pasquier, Emmanuelle Verger, Michiko Niwa-Kawakita, Valérie Lallemand-Breitenbach, Isabelle Plo, Jean-Jacques Kiladjian, Jean-Luc Villeval, Hugues de Thé.
      Interferon α (IFNα) is used to treat JAK2V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.
    DOI:  https://doi.org/10.1084/jem.20201268
  19. Clin Drug Investig. 2020 Oct 22.
    Concomitant Administration of Direct Oral Anticoagulants in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors.
    Alessandra Serrao, Emilia Scalzulli, Luciano Fiori, Alessio Di Prima, Massimo Breccia, Antonio Chistolini.
       BACKGROUND AND OBJECTIVE: In the last decades, the chronic myeloid leukemia (CML) therapeutic landscape has changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs), with 10-year survival rates improving to up to 80%. Long-lasting TKI treatment, in particular with second-generation TKIs, has enabled clinicians to manage the onset of several side effects and other co-morbidities, such as atrial fibrillation or venous thromboembolism (VTE).
    METHODS: We retrospectively evaluated nine CML patients treated with TKIs between 2017 and 2020 who experienced atrial fibrillation or VTE and received concomitant administration of TKIs and direct oral anticoagulants (DOACs) outside clinical trials, to evaluate the efficacy and safety of this combination.
    RESULTS: Median age was 66 years at CML diagnosis (range 52-73 years) and 69 years at the time of starting DOACs. A female predominance was observed. The median follow-up of concomitant DOAC and TKI administration was 8.5 months; edoxaban was administered in six patients and apixaban in two patients, and one patient received rivaroxaban. Regarding CML treatment, four patients received imatinib, two patients bosutinib, and three nilotinib. In eight patients DOACs were started for atrial fibrillation and in one patient for VTE. In none of the patients treated with the combination were additional symptomatic thrombotic adverse events or major bleedings reported.
    CONCLUSION: In this small case series, the use of DOACs in CML patients seemed feasible. Additional data on long-term outcomes including a larger cohort of CML patients treated with DOACs are, however, needed.
    DOI:  https://doi.org/10.1007/s40261-020-00980-w
  20. Sci Adv. 2020 Oct;pii: eabe5310. [Epub ahead of print]6(43):
    MCART1/SLC25A51 is required for mitochondrial NAD transport.
    Nora Kory, Jelmi Uit de Bos, Sanne van der Rijt, Nevena Jankovic, Miriam Güra, Nicholas Arp, Izabella A Pena, Gyan Prakash, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, David M Sabatini.
      The nicotinamide adenine dinucleotide (NAD+/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD+ transporter has been identified in yeast, how NAD enters mitochondria in metazoans is unknown. Here, we mine gene essentiality data from human cell lines to identify MCART1 (SLC25A51) as coessential with ETC components. MCART1-null cells have large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial levels of NAD+ and NADH. Isolated mitochondria from cells lacking or overexpressing MCART1 have greatly decreased or increased NAD uptake in vitro, respectively. Moreover, MCART1 and NDT1, a yeast mitochondrial NAD+ transporter, can functionally complement for each other. Thus, we propose that MCART1 is the long sought mitochondrial transporter for NAD in human cells.
    DOI:  https://doi.org/10.1126/sciadv.abe5310
  21. Leukemia. 2020 Oct 19.
    Evolving treatment patterns and outcomes in older patients (≥60 years) with AML: changing everything to change nothing?
    David Martínez-Cuadrón, Josefina Serrano, Cristina Gil, Mar Tormo, Pilar Martínez-Sánchez, José A Pérez-Simón, Raimundo García-Boyero, Carlos Rodríguez-Medina, María López-Pavía, Celina Benavente, Juan Bergua, Esperanza Lavilla-Rubira, María L Amigo, Pilar Herrera, Juan M Alonso-Domínguez, Teresa Bernal, Mercedes Colorado, María J Sayas, Lorenzo Algarra, María B Vidriales, Gabriela Rodríguez-Macías, Susana Vives, Manuel M Pérez-Encinas, Aurelio López, Víctor Noriega, María García-Fortes, Fernando Ramos, Juan I Rodríguez-Gutiérrez, Lisette Costilla-Barriga, Jorge Labrador, Blanca Boluda, Rebeca Rodríguez-Veiga, Joaquín Martínez-López, Miguel A Sanz, Pau Montesinos.
      There are no studies analyzing how therapeutic changes impact on outcomes of older AML patients. This study analyzes patient´s and disease characteristics, treatment patterns, and outcomes of 3637 AML patients aged ≥60 years reported to the PETHEMA registry. Study periods were 1999-2006 (before hypomethylating agents-HMAs availability) vs 2007-2013, and treatments were intensive chemotherapy (IC), non-intensive, clinical trial (CT), and supportive care only (SC). Median age was 72 (range, 60-99), 57% male, median ECOG 1 (range, 0-4), secondary AML 914 (30%), with adverse-risk genetic in 720 (32%). Treatment differed between study periods (1999-2006 vs 2007-2013): IC 58% vs 32%, non-intensive 1 vs 23%, CT 0 vs 2%, SC 27 vs 28% (p < 0.001). Median OS was 4.7 months (1-year OS 29% and 5-years 7%, without differences between periods), 1.2 for SC, 7.8 for non-intensive, 8.6 for IC, and 10.4 for CT (p < 0.001). OS improved in the 2007-2013 period for IC patients (10.3 vs 7.5 months, p = 0.004), but worsened for SC patients (1.2 vs 1.6 months, p = 0.03). Our real-life study shows that, despite evolving treatment for elderly patients during the last decade, OS has remained unchanged. Epidemiologic registries will critically assess whether novel therapies lead to noteworthy advances in the near future (#NCT02606825).
    DOI:  https://doi.org/10.1038/s41375-020-01058-4
  22. Cancer Discov. 2020 Oct 23.
    Hematopoietic Stem Cell Renewal Drives Myeloproliferative Neoplasms.
      Self-renewal and function of hematopoietic stem cells arose as possible drivers in genetic studies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-154
  23. Leuk Res. 2020 Sep 29. pii: S0145-2126(20)30163-6. [Epub ahead of print]98 106458
    The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.
    Paul W Manley, Louise Barys, Sandra W Cowan-Jacob.
      Asciminib is a potent, orally bioavailable, investigational drug that specifically and potently inhibits the tyrosine kinase activity of native ABL1, together with that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia (CML). In contrast to ATP-competitive BCR-ABL1 kinase inhibitors employed to treat CML that target multiple kinases, asciminib binds to the myristate binding pocket on the kinase domains of ABL1 and BCR-ABL1. Hitherto no drugs have been developed whose mechanism of action involves interacting with myristate binding pockets on proteins, and analysis of the structures of such binding sites in proteins other than ABL1/ABL2/BCR-ABL1 strongly suggest that asciminib will not bind to these with high affinity. Accordingly, the drug has no known safety liabilities resulting from any off-target activity, as illustrated by its specificity towards cells expressing BCR-ABL1 and lack of effects on non-kinase targets in biochemical screens. Because asciminib does not bind to the ATP-binding site it maintains substantial activity against kinase domain mutations that impart acquired drug resistance to ATP-competitive drugs. However, in vitro studies in cells have identified BCR-ABL1 mutations that reduce the anti-proliferative activity of asciminib, some of which are associated with clinical resistance towards the drug in patients. Here we review effects of asciminib on mutant forms of BCR-ABL1, analyse their sensitivity towards the drug from a structural perspective and affirm support for employing combinations with ATP-competitive inhibitors to impede the reactivation of BCR-ABL1 kinase activity in patients receiving monotherapy.
    Keywords:  Abelson (ABL1); Asciminib; BCR-ABL1; Chronic myeloid leukemia (CML); Drug resistance; Myristate; Tyrosine kinase inhibitor (TKI)
    DOI:  https://doi.org/10.1016/j.leukres.2020.106458
  24. Leuk Res. 2020 Oct 15. pii: S0145-2126(20)30167-3. [Epub ahead of print]99 106462
    Terminal deoxynucleotidyl transferase (TdT) expression is associated with FLT3-ITD mutations in Acute Myeloid Leukemia.
    Eleonora De Bellis, Tiziana Ottone, Lisa Mercante, Giulia Falconi, Elisa Cugini, Maria Irno Consalvo, Serena Travaglini, Giovangiacinto Paterno, Alfonso Piciocchi, Elisa Linnea Lindfors Rossi, Carmelo Gurnari, Luca Maurillo, Francesco Buccisano, William Arcese, Maria Teresa Voso.
      The terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in acute myeloid leukemias (AMLs), where it may be involved in the generation of NPM1 and FLT3-ITD mutations. We studied the correlations between TdT expression and FLT3-ITD or NPM1 mutations in primary AML samples, and the impact on patients' survival. TdT expression was analyzed in 143 adult AML patients by flow cytometry as percentage of positivity and mean fluorescence intensity (MFI) on blasts. TdT was positive in 49 samples (34.2%), with a median of 48% TdT-positivity (range 7-98) and a median MFI of 2.70 (range 1.23-30.54). FLT3-ITD and NPM1 mutations were present in 24 (16.7%) and 34 (23.7%) cases, respectively. Median TdT expression on blasts was significantly higher in FLT3-ITD+, as compared with FLT3-ITD- AMLs (median 8% vs 0% respectively, p = 0.035). NPM1 mutational status, FLT3-ITD allelic ratio, karyotype, and ELN risk groups, did not correlate with TdT expression or MFI on blasts. TdT + patients had poorer survival as compared to TdT-, but this result was not confirmed by the multivariable analysis, where ELN risk stratification as well as age and type of treatment remained independent prognostic factors for OS. In summary, our results support the possible implication of TdT enzyme in the generation of FLT3-ITD mutations in AML.
    Keywords:  FLT3-ITD mutations; acute myeloid leukemia; overall survival; terminal deoxynucleotidyl transferase; “filler” sequences
    DOI:  https://doi.org/10.1016/j.leukres.2020.106462
  25. Blood. 2020 Oct 22. 136(17): 1900-1901
    Rerouting DOT1L inhibitors in leukemia.
    Ross A Dickins.
      
    DOI:  https://doi.org/10.1182/blood.2020007352
  26. Genomics. 2020 Oct 16. pii: S0888-7543(20)31966-2. [Epub ahead of print]
    Comprehensive in-silico analysis of damage associated SNPs in hOCT1 affecting Imatinib response in chronic myeloid leukemia.
    Ismael Soltani, Wael Bahia, Assala Radhouani, Abdelkarim Mahdhi, Salima Ferchichi, Wassim Y Almawi.
      Non-synonymous single nucleotide polymorphisms (nsSNPs) in hOCT1 (encoded by SLC22A1 gene) are expected to affect Imatinib uptake in chronic myeloid leukemia (CML). In this study, sequence homology-based genetic analysis of a set of 270 coding SNPs identified 18 nsSNPs to be putatively damaging/deleterious using eight different algorithms. Subsequently, based on conservation of amino acid residues, stability analysis, posttranscriptional modifications, and solvent accessibility analysis, the possible structural-functional relationship was established for high-confidence nsSNPs. Furthermore, based on the modeling results, some dissimilarities of mutant type amino acids from wild-type amino acids such as size, charge, interaction and hydrophobicity were revealed. Three highly deleterious mutations consisting of P283L, G401S and R402G in SLC22A1 gene that may alter the protein structure, function and stability were identified. These results provide a filtered data to explore the effect of uncharacterized nsSNP and find their association with Imatinib resistance in CML.
    Keywords:  CML; Imatinib resistance; In silico analysis; hOCT1; nsSNP
    DOI:  https://doi.org/10.1016/j.ygeno.2020.10.007
  27. Leukemia. 2020 Oct 19.
    Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome.
    Sachin Kumar, Kalpana J Nattamai, Aishlin Hassan, Amanda Amoah, Rebekah Karns, Cuiping Zhang, Ying Liang, Akiko Shimamura, M Carolina Florian, Ute Bissels, Martha Luevano, Andreas Bosio, Stella M Davies, Medhanie Mulaw, Hartmut Geiger, Kasiani C Myers.
      Shwachman-Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small RhoGTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS HSC treated with GDF11 are transcriptionally more similar to control than to SDS HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.
    DOI:  https://doi.org/10.1038/s41375-020-01054-8
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