MYELOID NEOPLASIA AML1/RUNX1 functions as a cytoplasmic attenuator of NF- B signaling in the repression of myeloid tumors

Functional deregulation of transcription factors has been found in many types of tumors. Transcription factor AML1/RUNX1 is one of the most frequent targets of chromosomal abnormalities in human leukemia and altered function of AML1 is closely associated with malignant transformation of hematopoietic cells. However, the molecular basis and therapeutic targets of AML1-related leukemia are still elusive. Here, we explored immediate target pathways of AML1 by in vitro synchronous inactivation in hematopoietic cells. We found that AML1 inhibits NFB signaling through interaction with I B kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NFB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NFB signaling. Furthermore, inhibition of NFB signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. These findings reveal a novel role for AML1 as a cytoplasmic attenuator of NFB signaling and indicate that NFB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality. (Blood. 2011; 118(25):6626-6637)