PTPN11 Mutations in the Bone Marrow Microenvironment Induce Leukemia

Myeloproliferative neoplasms (MPN) are blood disorders which arise from the overproduction of myeloid cells by the bone marrow (BM). Mutations in the protein tyrosine phosphatase SHP2 (encoded by PTPN11) occur in approximately half of patients with Noonan syndrome, who have an increased risk of developing leukemias, including the childhood MPN juvenile myelomonocytic leukemia (JMML). To elucidate the role of Ptpn11 mutations in the murine BM microenvironment, Dong, Yu, Zheng, and colleagues interrogated a genetically engineered mouse model of Ptpn11 mutation–driven MPN which they had previously generated. Ptpn11^E76K/+Nestin-Cre⁺ mice, in which BM mesenchymal stem/progenitor cells (MSPC)—which are Nestin⁺—but not MPN cells expressed mutant Ptpn11, developed profound MPN. Further, expression of Ptpn11^E76K in both murine hematopoietic cells and BM stromal cells resulted in MPNs that were more severe and progressive than MPNs induced by the expression of Ptpn11^E76K in murine hematopoietic cells. Cell type–specific expression of Ptpn11^E76K identified MSPCs and osteoprogenitor cells as the BM cell types that induced MPN development. Ptpn11^E76K MSPCs and MPN cells were shown to overproduce, respectively, the C-C motif chemokine 3 (CCL3) and IL1β, both of which were also highly produced by PTPN11 mutant human MSPC and JMML cells. Ptpn11^E76K MSPC–derived CCL3 recruited monocytes to the area where MSPCs and hematopoietic stem cells (HSC) reside, and these monocytes released IL1β to hyperactivate HSCs and induce MPN. Consistent with these findings, treatment of MSPC-specific Ptpn11^E76K mice with CCL3 receptor antagonists reversed MPN-associated phenotypes. Together, these findings demonstrate how Ptpn11 mutations in the BM microenvironment drive MPN development and suggest that inhibiting CCL3 may prevent leukemic progression of MPN and improve stem cell transplantation therapy in patients with Noonan syndrome.

Dong L, Yu W-M, Zheng H, Loh ML, Bunting ST, Pauly M, et al. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 2016;539:304–8.

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