ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.

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.

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Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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Declaration of Interests R.L.L. is on the supervisory board of QIAGEN and is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, each of which include an equity interest. He receives research support from and has consulted for Celgene and Roche, has received research support from Prelude Therapeutics, and has consulted for Astellas, Incyte, Janssen, Morphosys, and Novartis. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews. The authors have filed a patent, EB19024, on the use of HDL-raising therapies in the treatment of myeloproliferative neoplasms.