ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms

Cell Rep. 2020 Mar 10;30(10):3397-3410.e5. doi: 10.1016/j.celrep.2020.02.056.

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.

Keywords: ATP-binding cassette transporter; cholesterol efflux; hematopoietic stem and progenitor cells; leukemia biology; somatic mutations; ten-eleven translocation 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / deficiency
  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / pathology
  • Cholesterol / metabolism
  • DNA-Binding Proteins / metabolism
  • Dioxygenases
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Interleukin-3 / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Lipoproteins, HDL / metabolism
  • Loss of Function Mutation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Myelopoiesis
  • Myeloproliferative Disorders / metabolism*
  • Myeloproliferative Disorders / pathology
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction
  • Splenomegaly / pathology

Substances

  • ABCA1 protein, human
  • ABCA1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • DNA-Binding Proteins
  • Interleukin-3
  • Lipoproteins, HDL
  • Proto-Oncogene Proteins
  • Cholesterol
  • Dioxygenases
  • Tet2 protein, mouse