Key Points TLR-activated FANCA- and

IL-1b suppresses in vitro expansion of Fancc-deficient multipotent hematopoietic progenitor cells. Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor a (TNF-a), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bonemarrow (BM) failure and selection of TNF-a–resistant leukemic stem cell clones. In macrophages, the TNF-a overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1b (IL-1b). Reasoning that IL-1bmight be involved in a like autoinhibitory loop, wedetermined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced over-production of both TNF-a and IL-1b in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1b potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-a overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1b is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1b or TNF-a alone. (Blood. 2013;122(18):3197-3205