Coordinated Regulation of Embryonic and Adult Hematopoietic Stem Cell Activity by PTPN11/Shp2.

Abstract 2630

Shp2, a tyrosine phosphatase with two SH2 domains, is implicated in malignant blood diseases. Germline dominant active mutations in PTPN11 that codes for Shp2 are found in approximately 50% of Noonan syndrome (NS) patients who have high risk of juvenile myelomonocytic leukemia (JMML). Somatic gain-of-function mutations in PTPN11 have also been detected in nonsyndromic JMML, pediatric AML, B-cell precursor ALL and myelodysplastic syndromes. The majority of leukemia-associated PTPN11 mutations disrupt the auto-inhibitory interactions between its N-terminal SH2 and the phosphatase domain, resulting in elevated catalytic activity. However, the physiological function of Shp2 in normal hematopoiesis in adults remains to be elucidated, although a Shp2 function in embryonic hematopoiesis was documented previously. Mouse embryonic stem cells (mESCs) homozygous for targeted exon 3 deletion are defective in differentiation to all blood cell lineages, suggesting its role in commitment/specification of hematopoietic stem cells (HSCs) during embryogenesis. Indeed, our previous experiments suggested a developmental blockage from mESC to mesoderm and hemangioblast differentiation by the exon 3 deletion. Notably, distinct mechanisms are involved in embryonic and adult hematopoiesis. Despite an essential role for specification of HSC fate from embryonic mesoderm, SCL/tal-1 was found dispensable for HSC maintenance and differentiation in adults. Similar observation was made for transcription factor Runx. We show here that inducible ablation of PTPN11/Shp2 in the hematopoietic compartment leads to severe cytopenia in bone marrow, spleen and periphery. Shp2 removal suppressed the number and function of HSCs and myeloid progenitors. Shp2-deficient HSCs failed to reconstitute irradiated recipient mice, due to combined defects in homing, self-renewal and survival. Therefore, PTPN11/Shp2 indeed plays an essential role in maintenance of a functional HSC pool in adult mammals. This study reveals a critical signaling component conserved in embryonic and adult hematopoiesis. Given the essential role of Shp2 in normal HSCs, developing a chemical that distinguishes wild-type and mutant Shp2 enzymes may be a therapeutic approach for elimination of leukemic stem cells (LSCs) harboring mutant PTPN11/Shp2.