Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis

Nat Med. 2012 Oct;18(10):1550-9. doi: 10.1038/nm.2958. Epub 2012 Sep 23.

Abstract

We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Base Sequence
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Cell Line
  • Cell Proliferation
  • Congenital Bone Marrow Failure Syndromes
  • Female
  • Granulocyte Colony-Stimulating Factor / metabolism*
  • Granulocytes / metabolism
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Myelopoiesis* / genetics
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Neutropenia / physiopathology
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Sequence Analysis, DNA
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Blood Proteins
  • HAX1 protein, human
  • HCLS1 protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • RNA, Small Interfering
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Granulocyte Colony-Stimulating Factor

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3

Associated data

  • GEO/GSE40712