Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

• Type of Material: Article
• Authors: Lei Dong, Emory University; Wen-Mei Yu, Emory University; Hong Zheng, Emory University; Mignon L. Loh, University of California San Francisco; Silvia Bunting, Emory University; Melinda Pauly, Emory University; Gang Huang, University of Cincinnati; Muxiang Zhou, Emory University; Hal E. Broxmeyer, Indiana University School of Medicine; David T. Scadden, Harvard University; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2016-11-10
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016, Rights Managed by Nature Publishing Group
• Final Published Version (URL): http://dx.doi.org/10.1038/nature20131
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 539
• Issue: 7628
• Start Page: 304
• End Page: +
• Grant/Funding Information: This work was supported by The National Institutes of Health grants HL130995 and DK092722 (to C.K.Q.).
• Keywords: SHP2 PTPN11; Multidisciplinary Sciences; MAINTENANCE; REGENERATION; PROGENITORS; HEMATOPOIETIC STEM; Science & Technology; MOUSE MODEL; Science & Technology - Other Topics; NOONAN-SYNDROME; CHRONIC MYELOGENOUS LEUKEMIA; RECEPTOR GENE; BONE-MARROW NICHE
• Research Categories: Health Sciences, Oncology

Abstract

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, 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. 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.