title: Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment.
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.
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Lei
authors: L
authors: Dong
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Wen-Mei
authors: WM
authors: Yu
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Hong
authors: H
authors: Zheng
authors: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of California at San Francisco, San Francisco, California 94122, USA.
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Pathology, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia 30322, USA.
authors: Silvia T
authors: ST
authors: Bunting
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Melinda
authors: M
authors: Pauly
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors: Gang
authors: G
authors: Huang
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Muxiang
authors: M
authors: Zhou
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors: Hal E
authors: HE
authors: Broxmeyer
authors: Center for Regenerative Medicine and MGH Cancer Center, Massachusetts General Hospital, Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Boston, Massachusetts 02114, USA.
authors: David T
authors: DT
authors: Scadden
authors: Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Cheng-Kui
authors: CK
authors: Qu
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D060833:Cellular Microenvironment / Q000235:genetics*; D054405:Chemokine CCL3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000473:pathology*; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics*; D033581:Stem Cell Transplantation
chemical_list: D054405:Chemokine CCL3; D053583:Interleukin-1beta; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse