ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • March 10, 2020

Research

keywords

  • ATP Binding Cassette Transporter 1
  • Myeloproliferative Disorders

Identity

PubMed Central ID

  • PMC7473128

Scopus Document Identifier

  • 85081000291

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2020.02.056

PubMed ID

  • 32160545

Additional Document Info

volume

  • 30

issue

  • 10