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
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Base Sequence
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Blood Proteins / genetics
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Blood Proteins / metabolism*
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Cell Line
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Cell Proliferation
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Congenital Bone Marrow Failure Syndromes
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Female
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Granulocyte Colony-Stimulating Factor / metabolism*
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Granulocytes / metabolism
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HEK293 Cells
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Humans
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Lymphoid Enhancer-Binding Factor 1 / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Myelopoiesis* / genetics
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Neutropenia / congenital*
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Neutropenia / genetics
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Neutropenia / physiopathology
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Phosphorylation
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RNA Interference
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RNA, Small Interfering
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Receptors, Granulocyte Colony-Stimulating Factor / genetics
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Sequence Analysis, DNA
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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Blood Proteins
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HAX1 protein, human
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HCLS1 protein, human
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LEF1 protein, human
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Lymphoid Enhancer-Binding Factor 1
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RNA, Small Interfering
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Receptors, Granulocyte Colony-Stimulating Factor
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Granulocyte Colony-Stimulating Factor
Supplementary concepts
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Neutropenia, Severe Congenital, Autosomal Recessive 3