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Kit and Scl regulation of hematopoietic stem cells

Rojas-Sutterlin, Shantia,b; Lecuyer, Ericc,d; Hoang, Tranga,b,d,e

Current Opinion in Hematology: July 2014 - Volume 21 - Issue 4 - p 256–264
doi: 10.1097/MOH.0000000000000052
HEMATOPOIESIS: Edited by Hal E. Broxmeyer

Purpose of review KIT tyrosine kinase receptor is essential for several tissue stem cells, especially for hematopoietic stem cells (HSCs). Moderately decreased KIT signaling is well known to cause anemia and defective HSC self-renewal, whereas gain-of-function mutations are infrequently found in leukemias. Thus, maintaining KIT signal strength is critically important for homeostasis. KIT signaling in HSCs involves effectors such as SHP2 and PTPN11. This review summarizes the recent developments on the novel mechanisms regulating or reinforcing KIT signal strength in HSCs and its perturbation in polycythemia vera.

Recent findings Stem cell leukemia (SCL) is a transcription factor that is essential for HSC development. Genetic experiments indicate that Kit, protein tyrosine phosphatase, nonreceptor type 11 (Ptpn11), or Scl control long-term HSC self-renewal, survival, and quiescence in adults. Kit is now shown to be centrally involved in two feedforward loops in HSCs, one with Ptpn11 and the other with Scl.

Summary Knowledge of the regulatory mechanisms that favor self-renewal divisions or a lineage determination process is central to the design of strategies to expand HSCs for the purpose of cell therapy. In addition, transcriptome and phosphoproteome analyses of erythroblasts in polycythemia vera identified lower SCL expression and hypophosphorylated KIT, suggesting that the KIT–SCL loop is relevant to the pathophysiology of human blood disorders as well.

aInstitute of Research in Immunology and Cancer, University of Montreal

bMolecular Biology Program, Faculty of Medicine, University of Montreal

cInstitut de Recherches Cliniques de Montreal (IRCM)

dDepartment of Biochemistry

eDepartment of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Correspondence to Trang Hoang, PhD, Institute for Research in Immunology and Cancer (IRIC), University of Montréal, P.O. Box 6128, Downtown Station, Montréal, QC, Canada H3C 2J7. Tel: +1 514 343 6970; e-mail: trang.hoang@umontreal.ca

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins