Non-Lineage/Stage Restricted Effects of a Gain-of-Function Mutation in Tyrosine Phosphatase Ptpn11 (Shp2) on Malignant Transformation of Hematopoietic Cells

Abstract 392

SHP2, a protein tyrosine phosphatase implicated in multiple cell signaling processes, plays an essential role in hematopoietic cell development. Our previous studies have demonstrated that this phosphatase is required for erythroid, myeloid, and lymphoid development and that it functions in cytokine signaling in both catalytically-dependent and –independent manners. Notably, germline and somatic mutations (heterozygous) in PTPN11 (encoding SHP2) have been identified in 35% of the patients with juvenile myelomonocytic leukemia (JMML), a childhood myeloproliferative disorder (MPD). Furthermore, PTPN11 mutations are also found in pediatric myelodysplastic syndromes (10%), B cell lymphoblastic leukemia (B-ALL) (7%), acute myeloid leukemia (AML) (4%), and sporadic solid tumors. These mutations result in hyperactivation of SHP2 catalytic activity. In addition, PTPN11 disease mutations, especially leukemia mutations, enhance the binding of mutant SHP2 to signaling partners. Although previous studies have shown that Ptpn11 mutations induce cytokine hypersensitivity in myeloid progenitors and MPD in mice, it is unclear whether Ptpn11 mutations also play a causal role in the pathogenesis of acute leukemias. If so, the underlying mechanisms and the cell origin of leukemia initiating/stem cells (LSCs) remain to be determined. PTPN11^E76K mutation is the most common and most active PTPN11 mutation found in JMML and acute leukemias. However, the pathogenic effects of this mutation have not been well characterized. We created Ptpn11^E76K conditional knock-in mice. Global Ptpn11^E76K/+ mutation resulted in early embryonic lethality associated with enhanced ERK signaling. Induced knock-in of this mutation in pan hematopoietic cells led to MPD as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors. These animals subsequently progressed to acute leukemias. Intriguingly, in addition to AML, T-ALL and B-ALL were evolved. PTPN11^E76K/+ mutation induced LSC development not only in stem cells but also in lineage committed progenitors as tissue-specific knock-in of Ptpn11^E76K/+ mutation in myeloid, T lymphoid, and B lymphoid progenitors also resulted in AML, T-ALL, and B-ALL, respectively. Further analyses revealed that Shp2 was distributed to centrosomes and that Ptpn11^E76K/+ mutation promoted LSC development partly by causing centrosome amplification and genomic instability. Thus, Ptpn11^E76K mutation has non-lineage specific effects on malignant transformation of hematopoietic cells and initiates acute leukemias at various stages of hematopoiesis. This mutation may play an initiating role in the pathogenesis of pediatric acute leukemias.