Fancc-deficient hematopoietic progenitors are hypersensitive to IL-1β. (A) Wild-type or Fancc^−/− KLS cells were isolated and, based on percent of the KLS cells also bearing the CD34^–Flt3^– signature (LT-HSCs), were plated at 1000 LT-HSCs per well in 500 µL RPMI/10% FBS containing IL-6, IL-11, SCF, and FLT3L. Cells were treated with murine IL-1β (30 pg/mL) or medium alone for 7 days. Total cells and LT-HSCs were then counted using flow cytometry. Shown is the mean number of LT-HSCs per 10⁶ total cells in each set of duplicate wells after 7 days. The percent difference in the LT-HSC population in IL-1β–treated cells compared with untreated cells is indicated above each bar that represents the number of LT-HSCs observed after IL-1β treatment. The results of 4 independent experiments are shown. (B) Data from these 4 experiments were pooled and expressed as the percent difference in the LT-HSC population in IL-1β-treated cells compared with untreated cells. (C) A model of the proposed IL-1β–mediated autoinhibitory loop is shown. The FA mononuclear phagocyte (MΦ) pool overproduces IL-1β in response to TLR stimulation, and the FA hematopoietic stem and progenitor cell (HSC/HPC) pool fails to sustain self-replicative activity and therefore contracts as a result of intrinsic IL-1β hypersensitivity. TLR-stimulated normal mononuclear phagocytes produce normal levels of IL-1β, and the normal HSC/HPCs are more tolerant of IL-1β.