CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216.
| Title: | CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216. |
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| Authors: | Gress V; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Roussy M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Boulianne L; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Department of Pathology, McGill University, Montréal, QC, Canada.; Bilodeau M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Cardin S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; El-Hachem N; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Lisi V; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Khakipoor B; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Rouette A; Molecular Diagnostic Laboratory, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada.; Farah A; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Théret L; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Aubert L; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Fatima F; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Department of Pathology, McGill University, Montréal, QC, Canada.; Audemard É; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Thibault P; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Bonneil É; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Chagraoui J; Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer, Montréal, Québec, Canada.; Laramée L; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Gendron P; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Jouan L; Molecular Diagnostic Laboratory, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada.; Jammali S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Paré B; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Simpson SM; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Tran TH; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Duval M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Teira P; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Bittencourt H; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Santiago R; Division of Hematology-Oncology, Centre Hospitalier Universitaire de Québec-Université Laval, Québec City, QC, Canada.; Centre de recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec City, QC, Canada.; Barabé F; Centre de recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec City, QC, Canada.; Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.; Sauvageau G; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer, Montréal, Québec, Canada.; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada.; Smith MA; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Hébert J; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Division of Hematology-Oncology and Quebec Leukemia Cell Bank, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.; Roux PP; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Gruber TA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.; Lavallée VP; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Wilhelm BT; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Cellot S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. |
| Source: | Blood advances [Blood Adv] 2024 Jan 09; Vol. 8 (1), pp. 112-129. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Society of Hematology, [2016]- |
| MeSH Terms: | Leukemia, Megakaryoblastic, Acute*/drug therapy ; Leukemia, Megakaryoblastic, Acute*/genetics ; Leukemia, Megakaryoblastic, Acute*/pathology ; Antineoplastic Agents*; Humans ; Child ; Child, Preschool ; Animals ; Mice ; Proteomics ; Transcription Factors ; Proto-Oncogene Proteins c-bcl-2 ; Repressor Proteins ; Aniline Compounds ; Sulfonamides ; Piperazines |
| Abstract: | Abstract: Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted, and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two-thirds of the cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest-fatality subgroups. We established CD34+ cord blood-derived CG2 models (n = 6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia-initiating cell frequencies, comutational landscape, and gene expression signature, with distinct upregulation of the prosurvival factor B-cell lymphoma 2 (BCL2). Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared with CD34+ cells (eg, NCAM1 and CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single-cell profiling. Although CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with venetoclax, they were vulnerable to strategies that target the megakaryocytic prosurvival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor navitoclax and DT2216, a selective BCL-XL proteolysis-targeting chimera degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low-dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.; (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
| References: | Genes Chromosomes Cancer. 2006 May;45(5):437-46. (PMID: 16419055); J Exp Med. 2012 Oct 22;209(11):2017-31. (PMID: 23045605); Cancer Cell. 2017 Mar 13;31(3):452-465. (PMID: 28292442); Nat Commun. 2019 May 16;10(1):2189. (PMID: 31097698); Blood Adv. 2020 Oct 27;4(20):5050-5061. (PMID: 33080007); Cancer Discov. 2020 Apr;10(4):536-551. (PMID: 31974170); Hum Gene Ther. 2004 Oct;15(10):976-88. (PMID: 15585113); Blood. 2017 Jun 22;129(25):3344-3351. (PMID: 28408459); Trends Cancer. 2017 Sep;3(9):631-642. (PMID: 28867167); Crit Rev Oncol Hematol. 2019 Jun;138:132-138. (PMID: 31092368); Blood. 2014 Dec 4;124(24):3608-12. (PMID: 25339361); Blood. 2015 Aug 20;126(8):943-9. (PMID: 26186939); Blood Adv. 2019 Nov 12;3(21):3307-3321. (PMID: 31698461); Leukemia. 2016 Oct;30(10):2077-2080. (PMID: 27133823); Cell. 2011 Mar 4;144(5):646-74. (PMID: 21376230); Genes Chromosomes Cancer. 2018 Jun;57(6):311-319. (PMID: 29427526); Lancet Oncol. 2020 Apr;21(4):551-560. (PMID: 32171069); Cancer Cell. 2012 Nov 13;22(5):683-97. (PMID: 23153540); Future Oncol. 2018 Sep;14(21):2115-2129. (PMID: 29595064); Blood Adv. 2019 Dec 23;3(24):4326-4335. (PMID: 31869416); Lancet Oncol. 2010 Dec;11(12):1149-59. (PMID: 21094089); Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):1-9. (PMID: 33275682); Nat Genet. 2007 Aug;39(8):1018-24. (PMID: 17618285); Am J Hematol. 2019 Oct;94(10):E253-E255. (PMID: 31259427); Cancer Discov. 2019 Dec;9(12):1736-1753. (PMID: 31662298); Leukemia. 2013 Dec;27(12):2280-8. (PMID: 23531517); Pediatr Blood Cancer. 2023 May;70(5):e30251. (PMID: 36789545); Cancer Discov. 2021 Jun;11(6):1440-1453. (PMID: 33593877); Nat Rev Cancer. 2016 Feb;16(2):99-109. (PMID: 26822577); Front Cell Dev Biol. 2023 Jun 01;11:1170622. (PMID: 37325571); Dev Cell. 2013 Jan 28;24(2):144-58. (PMID: 23318133); Nat Commun. 2020 Jul 24;11(1):3701. (PMID: 32709883); Cell. 2012 Aug 3;150(3):575-89. (PMID: 22863010); Leuk Res. 2003 Feb;27(2):165-71. (PMID: 12526922); Blood. 2023 Mar 30;141(13):1610-1625. (PMID: 36508699); EMBO J. 2012 Mar 21;31(6):1494-505. (PMID: 22266796); Blood Adv. 2022 Nov 22;6(22):5933-5937. (PMID: 36149945); Blood Adv. 2022 Jun 28;6(12):3626-3631. (PMID: 35286394); Blood. 2012 Jun 14;119(24):5850-8. (PMID: 22374700); Am J Hematol. 2015 Oct;90(10):963. (PMID: 26148249); Cancer Res. 2008 May 1;68(9):3421-8. (PMID: 18451170); Pediatr Blood Cancer. 2021 Nov;68(11):e29221. (PMID: 34260140); Exp Hematol. 2018 Dec;68:51-61. (PMID: 30243574); Cancer Cell. 2018 Dec 10;34(6):879-891. (PMID: 30537511); Cell. 2019 Mar 7;176(6):1265-1281.e24. (PMID: 30827681); Blood. 2013 Apr 25;121(17):3469-72. (PMID: 23407549); Nat Genet. 2017 Mar;49(3):451-456. (PMID: 28112737); Cell Death Dis. 2021 Feb 26;12(2):222. (PMID: 33637708); Cell Death Dis. 2020 Jan 6;11(1):8. (PMID: 31907357); Leukemia. 2023 Mar;37(3):571-579. (PMID: 36585521); Mol Cell Biol. 2005 Dec;25(23):10235-50. (PMID: 16287841); J Clin Invest. 2022 Nov 15;132(22):. (PMID: 36136600); Blood. 1995 Aug 15;86(4):1348-55. (PMID: 7632941); Haematologica. 2020 Mar;105(3):708-720. (PMID: 31296572); Front Pediatr. 2019 Oct 15;7:401. (PMID: 31681706); Mol Clin Oncol. 2023 Jan 31;18(3):18. (PMID: 36798463); Cell. 2007 Mar 23;128(6):1173-86. (PMID: 17382885); Nat Genet. 2001 Jul;28(3):220-1. (PMID: 11431691); Mol Cell. 2020 Jun 18;78(6):1045-1054. (PMID: 32516599); J Exp Med. 2011 Sep 26;208(10):2017-31. (PMID: 21911424); Nat Med. 2019 Dec;25(12):1938-1947. (PMID: 31792461); Blood. 1991 Aug 1;78(3):748-52. (PMID: 1859887); Clin Cancer Res. 2020 Feb 1;26(3):726-737. (PMID: 31719049); Cancer Discov. 2014 Sep;4(9):1074-87. (PMID: 24994123); Cancer Chemother Pharmacol. 2014 Sep;74(3):593-602. (PMID: 25053389); Nat Rev Mol Cell Biol. 2019 Mar;20(3):175-193. (PMID: 30655609); Blood. 2020 Mar 12;135(11):791-803. (PMID: 31932844); Cell Death Differ. 2018 Jan;25(1):37-45. (PMID: 29099482) |
| Substance Nomenclature: | 0 (Transcription Factors); 0 (Antineoplastic Agents); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Repressor Proteins); XKJ5VVK2WD (navitoclax); 0 (Aniline Compounds); 0 (Sulfonamides); 0 (DT2216); 0 (Piperazines); 0 (CBFA2T3 protein, human) |
| Entry Date(s): | Date Created: 20230920 Date Completed: 20231229 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10787250 |
| DOI: | 10.1182/bloodadvances.2022008899 |
| PMID: | 37729615 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't