Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells.
Surviving irf8 mutants quickly developed a myeloproliferative neoplasm (MPN)-like disease with enhanced output of the myeloid precursors, which recurred after transplantation.
Over time this MPD progresses to acute myeloid leukemia (AML), suggesting that ICSBP deficiency is adequate for MPD, but additional genetic lesions are required for AML.
These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K-dependent ICSBP phosphorylation.
Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder.