Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

• Published in: Nature (London) Vol. 539; no. 7628; pp. 304 - 308
• Main Authors: Dong, Lei, Yu, Wen-Mei, Zheng, Hong, Loh, Mignon L., Bunting, Silvia T., Pauly, Melinda, Huang, Gang, Zhou, Muxiang, Broxmeyer, Hal E., Scadden, David T., Qu, Cheng-Kui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2016; Nature Publishing Group
• Subjects: 631/532/1542; 692/420/755; Animals; Blood; Bone marrow; Cell Transformation, Neoplastic - genetics; Cellular Microenvironment - genetics; Chemokine CCL3 - antagonists & inhibitors; Chemokine CCL3 - metabolism; Chemokines; Disease Progression; Endothelial Cells - cytology; Female; Gene mutation; Genetic aspects; Health aspects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humanities and Social Sciences; Humans; Interleukin-1beta - metabolism; letter; Leukemia; Leukemia - genetics; Leukemia - pathology; Leukemia, Myelomonocytic, Juvenile - genetics; Leukemia, Myelomonocytic, Juvenile - metabolism; Leukemia, Myelomonocytic, Juvenile - pathology; Male; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Mice; Monocytes - metabolism; multidisciplinary; Mutation; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Noonan Syndrome - pathology; Osteoblasts - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Science; Stem Cell Niche - genetics; Stem Cell Transplantation; Stem cells; Studies; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20131

Mutations in the protein tyrosine phosphatase SHP2 affect cells in the bone marrow environment, which leads to aberrant activation of resident haematopoietic stem cells and thereby contributes to the development of leukaemia. A mutated microenvironment in leukaemia Hereditary mutations in the tyrosine phosphatase SHP2 (encoded by PTPN11 ), part of the Ras signalling pathway, have been linked to a syndrome leading to an increased risk of developing leukaemia. Previous studies in mouse models have shown that the function of haematopoietic stem cells carrying these mutations is defective, which suggests a cell-autonomous effect. Cheng-Kui Qu and colleagues find that the mutations also affect cells in the bone marrow environment, blocking their normal control on haematopoietic stem cells and thereby promoting the development of leukaemia. Administration of CCL3 receptor antagonists effectively reversed oncogenesis driven by the Ptpn11 -mutated bone marrow microenvironment. Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11 ), a positive regulator of the RAS signalling pathway 1 , are found in 50% of patients with Noonan syndrome 2 . These patients have an increased risk of developing leukaemia 3 , especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity 4 , 5 , 6 , 7 . However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11 -mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.