title: Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.
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.
authors.affiliation: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany. skokowa.julia@mh-hannover.de
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Maxim
authors.initials: M
authors.lastname: Klimiankou
authors.forename: Olga
authors.initials: O
authors.lastname: Klimenkova
authors.forename: Dan
authors.initials: D
authors.lastname: Lan
authors.forename: Kshama
authors.initials: K
authors.lastname: Gupta
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Esteban
authors.initials: E
authors.lastname: Carrizosa
authors.forename: Inna
authors.initials: I
authors.lastname: Kusnetsova
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
authors.forename: Claudio
authors.initials: C
authors.lastname: Sustmann
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Kreipe
authors.forename: Janis
authors.initials: J
authors.lastname: Burkhardt
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D000080984:Congenital Bone Marrow Failure Syndromes; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C104759:HAX1 protein, human; C061909:HCLS1 protein, human; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D034741:RNA, Small Interfering; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor