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

• Published in: Nature medicine Vol. 18; no. 10; pp. 1550 - 1559
• Main Authors: Skokowa, Julia, Klimiankou, Maxim, Klimenkova, Olga, Lan, Dan, Gupta, Kshama, Hussein, Kais, Carrizosa, Esteban, Kusnetsova, Inna, Li, Zhixiong, Sustmann, Claudio, Ganser, Arnold, Zeidler, Cornelia, Kreipe, Hans-Heinrich, Burkhardt, Janis, Grosschedl, Rudolf, Welte, Karl
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2012; Nature Publishing Group
• Subjects: 631/250/232; 631/45/475/2290; 692/699/1541; Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autoimmune diseases; Base Sequence; Biomedical and Life Sciences; Biomedicine; Blood Proteins - genetics; Blood Proteins - metabolism; Bone marrow; Cancer Research; Cell Line; Cell Proliferation; Female; Gene expression; Genetic aspects; Genetic disorders; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - metabolism; Granulocytes - metabolism; HEK293 Cells; Humans; Infectious Diseases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukocytes; Lymphoid Enhancer-Binding Factor 1 - metabolism; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Mutagenesis; Mutation; Myelopoiesis - genetics; Neurosciences; Neutropenia - congenital; Neutropenia - genetics; Neutropenia - physiopathology; Phosphorylation; Physiological aspects; Receptors, Granulocyte Colony-Stimulating Factor - genetics; Risk factors; RNA Interference; RNA, Small Interfering; Sequence Analysis, DNA; Signal Transduction; Testing laboratories; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2958

In congenital neutropenia, myeloid-lineage differentiation in response to the cytokine G-CSF is defective. Julia Skokowa et al . now show that an interplay among three proteins—the adapter proteins HCLS1 and HAX1 and the transcription factor LEF-1—is required for G-CSF–triggered granulocytic differentiation, and they provide evidence that this pathway is dysregulated in both congenital neutropenia and acute myeloid leukemia. 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 .