PTPN11 Mutations in the Bone Marrow Microenvironment Induce Leukemia

2016 Cancer Discovery  
Major finding: L-arginine controls T-cell metabolism and promotes T-cell survival to enhance antitumor immunity. Approach: High-resolution mass spectrometry characterized the proteome and metabolome of activated T cells. Impact: L-arginine enhances antitumor T-cell responses and may potentially improve T-cell therapies. Metabolism L-ARGININE REGULATES T-CELL METABOLISM TO PROMOTE ANTITUMOR ACTIVITY T-cell survival and antitumor activity are dependent on metabolic fitness, and activated T cells
more » ... dapt their metabolism to use large amounts of glucose, amino acids, and fatty acids. To characterize metabolic adaptations underlying T-cell activation, Geiger and colleagues used highresolution mass spectrometry to analyze the proteome and metabolome of human primary naïve T cells. A total of 2,824 differentially expressed proteins were identified in activated T cells compared with nonactivated T cells, and upregulated proteins included enzymes involved in several metabolic pathways including arginine metabolism. Of 429 identified metabolites, 49 were increased upon T-cell activation and only 14 were decreased, including three members of the same metabolic pathway: arginine, ornithine, and N-acetylornithine. T-cell activation resulted in a rapid decrease in intracellular arginine despite enhanced L-arginine uptake due to the rapid conversion of L-arginine into downstream metabolites, mainly by the mitochondrial enzyme arginase 2 (ARG2), which was upregulated in activated T cells. T cells activated in L-arginine-supplemented medium consumed less glucose and exhibited reduced expression of glucose transporters and glycolytic enzymes, altogether indicating that L-arginine reduced glycolytic flux. Conversely, oxidative phosphorylation was enhanced by increased intracellular L-arginine in activated T cells. In addition to the metabolic affects, L-arginine infl uenced the fate of activated T cells; elevated L-arginine levels limited T-cell differentiation and promoted the maintenance of central-memory T-cell characteristics. Further, L-arginine increased the survival of activated CD4 + and CD8 + T cells. In vivo, supplementation with L-arginine enhanced activated T-cell survival, and adoptive transfer of L-arginine-treated cells activated by tumor antigen resulted in an enhanced antitumor response in melanoma xenografts. Together, these fi ndings indicate that L-arginine promotes T-cell survival and antitumor activity and suggest that L-arginine may have the potential to enhance T-cell therapies. ■ Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167:829-42.e13. Major finding: Ptpn11 activating mutations in bone marrow MSPCs and osteoprogenitors induce MPN in mice. Mechanism: Ptpn11 mutant cells produce CCL3 to recruit monocytes which secrete cytokines to activate HSCs. Impact: CCL3 is a potential target for inhibiting Noonan syndrome-associated leukemogenesis. Myeloproliferative neoplasms (MPN) are blood disorders which arise from the o verproduction 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-specifi c expression of Ptpn11 E76K identifi ed 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 fi ndings, treatment of MSPC-specifi c Ptpn11 E76K mice with CCL3 receptor antagonists reversed MPN-associated phenotypes. Together, these fi ndings 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. ■
doi:10.1158/ fatcat:iviwfhd6wvaa5ligljfvhgcxbe