Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors. Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

Germline mutations in ETV6 are associated with a syndrome of thrombocytopenia and leukemia predisposition, and ETV6 is among the most commonly mutated genes in leukemias, especially childhood B cell acute lymphoblastic leukemia. However, the mechanisms underlying disease due to ETV6 dysfunction are poorly understood. In order to address these gaps in knowledge, using CRISPR/Cas9, we developed a mouse model of the most common recurrent, disease-causing germline mutation in ETV6, which recapitulates aspects of human disease. We found defects in hematopoiesis, primarily related to abnormalities of the multipotent progenitor population 4 (MPP4) subset of hematopoietic progenitor cells and evidence of sterile inflammation. Expression of ETV6 in Ba/F3 cells altered the expression of several cytokines, some of which were also detected at higher levels in the bone marrow of the mice with Etv6 mutation. Among these, IL-18 and IL-13 abrogated B cell development of sorted MPP4 cells, but not common lymphoid progenitors, suggesting that inflammation contributes to abnormal hematopoiesis by impairing lymphoid development. These data, along with that from humans, support a model in which ETV6 dysfunction promotes inflammation, which adversely affects thrombopoiesis and promotes leukemogenesis. Overall design: hematopoietic progenitor populations were sorted by flow cytometry from mice with wild type (n=3 mice) and homozygous mutation in Etv6 (h.P214L) (n=4 mice)