Role of SHP2 in hematopoiesis and leukemogenesis

Abstract

Purpose of review: SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it.

Recent findings: Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a noncell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an 'undruggable' target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies.

Summary: SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.

Figure 1

SHP2 regulates RUNX1 interaction with GATA1 and SWI/SNF chromatin remodeling complex during megakaryocyte and T cell differentiation. The auto-inhibitory domain of RUNX1 is phosphorylated by SFK in progenitor cells and is dephosphorylated by SHP2.

Figure 2

Constitutive activation of SHP2 suppresses the phosphorylation of HoxA9 in response to differentiation inducing cytokines during myelopoiesis. This leads to increased expression of CDX4 transcription factor and block in differentiation.

Figure 3

Expression of mutant Ptpn11 in MSC and osteo-progenitor cells leads to donor cell derived myeloproliferation. Mutant Ptpn11 expressing MSC and osteo-progenitor cells have increased secretion of chemokine, CCL3 which recruits inflammatory IL-1β secreting monocytes to the HSC niche. These changes in the niche contribute to loss of HSC quiescence and increased myeloid lineage commitment.