ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms

• DOI: 10.1016/j.celrep.2020.02.056
• Publication Date: 2020-03-10T15:10:59Z
• Authors: Manon Viaud; Omar Abdel-Wahab; Julie Gall; Stoyan Ivanov; Rodolphe Guinamard; Sophie Sore; Johanna Merlin; Marion Ayrault; Emma Guilbaud; Arnaud Jacquel; Patrick Auberger; Nan Wang; Ross L. Levine; Alan R. Tall; Laurent Yvan-Charvet
• Keywords: 0301 basic medicine; QH301-705.5; [SDV]Life Sciences [q-bio]; Article; Dioxygenases; Mice; 03 medical and health sciences; Loss of Function Mutation; Cell Line, Tumor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Proto-Oncogene Proteins; Animals; Humans; Biology (General); Myelopoiesis; Myeloproliferative Disorders; Hematopoietic Stem Cells; 3. Good health; [SDV] Life Sciences [q-bio]; DNA-Binding Proteins; Mice, Inbred C57BL; Cell Transformation, Neoplastic; Cholesterol; Splenomegaly; Interleukin-3; Lipoproteins, HDL; ATP Binding Cassette Transporter 1; Signal Transduction

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis.