Cleaning up the environment in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a commonly fatal myeloid leukemia occurring in very young children bearing germline or somatic mutations in genes within the RAS-ERK signaling pathway including NF1, CBL, KRAS, NRAS, and PTPN11 (1). Leukemia relapse following allogeneic stem cell transplant is uncharacteristically high at 40–50% for JMML patients, and findings from the recently published manuscript by Dong et al. (2) provide some clues that might account for this high relapse rate. The authors found that Nestin-Cre-mediated knock-in of Ptpn11E76K/+, resulting in mutant Shp2 expression in bone marrow (BM) mesenchymal stem/progenitor and neural cells, induced activation of otherwise normal hematopoietic stem and progenitor cells to differentiate into myeloid cells. The resulting leukemia recapitulated the features of JMML, with splenomegaly, myelocytosis, and increased myelopoiesis in the BM. While Mx1-Cre- and LysM-Cre-mediated knock-in of Ptpn11E76K/+ have previously been shown to cause a JMML-like myeloproliferative neoplasm (MPN) in mice (3), this is the first study demonstrating that BM niche-restricted expression of Ptpn11E76K/+ is capable of producing disease. The elegance of the present study lies in the use of five tissue-specific Cre promoters which identified mesenchymal stem/progenitor cells and osteoprogenitors as the critical mutated BM microenvironment cell types with the capacity to promote myeloid disease, ruling out differentiated osteoblasts and endothelial cells