1. CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216.
- Author
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Gress V, Roussy M, Boulianne L, Bilodeau M, Cardin S, El-Hachem N, Lisi V, Khakipoor B, Rouette A, Farah A, Théret L, Aubert L, Fatima F, Audemard É, Thibault P, Bonneil É, Chagraoui J, Laramée L, Gendron P, Jouan L, Jammali S, Paré B, Simpson SM, Tran TH, Duval M, Teira P, Bittencourt H, Santiago R, Barabé F, Sauvageau G, Smith MA, Hébert J, Roux PP, Gruber TA, Lavallée VP, Wilhelm BT, and Cellot S
- Subjects
- Humans, Child, Child, Preschool, Animals, Mice, Proteomics, Transcription Factors, Proto-Oncogene Proteins c-bcl-2, Repressor Proteins, Leukemia, Megakaryoblastic, Acute drug therapy, Leukemia, Megakaryoblastic, Acute genetics, Leukemia, Megakaryoblastic, Acute pathology, Antineoplastic Agents
- 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.)
- Published
- 2024
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