SHP-2 and myeloid malignancies

This review focuses on the non-receptor Src-homology 2 domain-containing protein tyrosine phosphatase SHP-2 and its role in signal transduction, hematopoiesis, and leukemogenesis. Specifically, we discuss the role of inherited and somatic mutations that result in SHP-2 gain-of-function in human disease, including myeloid malignancies.

Up-regulation of RAS signaling is a major perturbation that drives the aberrant growth of malignant myeloid cells. Leukemia-associated SHP-2 mutations define a novel type of molecular events resulting in hyperactive RAS function.

SHP-2 plays an important role in intracellular signaling elicited by growth factors, hormones, and cytokines, and it is required during development and hematopoiesis. Gain of function mutations in PTPN11, the gene encoding SHP-2, is observed in Noonan syndrome and related development disorders, as well as in myeloid malignancies. Fully characterizing the incidence and spectrum of PTPN11 mutations in hematologic malignancies, and in other forms of cancer, is an area of active investigation.