Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

ABSTRACT: Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GVHD (cGVHD) carrying persistent CD4+ T cell clonal expansion which harbored somatic mTOR, NFKB2, and TLR2 mutations. Functional analysis of the discovered mTOR mutation indicated a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements supported increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggested mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest that som

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Satu Musjoki 

PROVIDER: E-MTAB-8911 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress