Shp2 function in hematopoietic stem cell biology and leukemogenesis

Abstract

Purpose of review: The protein tyrosine phosphatase Shp2 is encoded by PTPN11 and positively regulates physiologic hematopoiesis. Mutations of PTPN11 cause the congenital disorder Noonan syndrome and pathologically promote human leukemias. Given the high frequency of PTPN11 mutations in human disease, several animal models have been generated to investigate Shp2 in hematopoietic stem cell (HSC) function and leukemic transformation.

Recent findings: Two independent animal models bearing knockout of Shp2 in hematopoietic tissues clearly demonstrate the necessity of Shp2 in HSC repopulating capacity. Reduced HSC quiescence and increased apoptosis accounts for diminished HSC function in the absence of Shp2. The germline mutation Shp2D61G enhances HSC activity and induces myeloproliferative disease (MPD) in vivo by HSC transformation. The somatic mutation Shp2D61Y produces MPD in vivo but fails to induce acute leukemia, whereas somatic Shp2E76K produces MPD in vivo that transforms into full-blown leukemia. HSCs expressing Shp2D61Y do not generate MPD in recipient animals upon transplantation, whereas Shp2E76K-expressing HSCs yield MPD as well as acute leukemia in recipient animals. The mechanisms underlying the unique functions of Shp2D61Y and Shp2E76K in HSC transformation and leukemogenesis continue to be under investigation.

Summary: Further understanding of the physiologic and pathologic role of Shp2 in hematopoiesis and leukemogenesis, respectively, will yield information needed to develop therapeutic strategies targeted to Shp2 in human disease.

FIGURE 1

Schematic diagram comparing the hematopoietic progenitor, hematopoietic stem cell, and leukemia transformation phenotypes of murine models bearing knockout of Shp2 (a), germline knockin of Shp2D61G (b), somatic knockin of Shp2D61Y (c), or somatic knockin of Shp2E76K (d). BM, bone marrow; HSC, hematopoietic stem cell; LSK, Lin-negative Sca1-positive Kit-positive; MPD; myeloproliferative disorder; PB, peripheral blood; WBC, white blood cell.