Role of the RUNX1‐EVI1 fusion gene in leukemogenesis

RUNX1‐EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1‐EVI1 has oncogenic potentials through dominant‐negative effect over wild‐type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP‐1, suppression of TGF‐β‐mediated growth inhibition and repression of C/EBPα. Runx1‐EVI1 heterozygous knock‐in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1–/– mice do, indicating that RUNX1‐EVI1 dominantly suppresses functions of wild‐type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1‐EVI1, and a Runx1‐EVI1 knock‐in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1‐EVI1 plays indispensable roles in leukemogenesis of t(3;21)‐positive leukemia. Major leukemogenic effect of RUNX1‐EVI1 is mainly through histone deacetyltransferase recruitment via C‐terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1‐EVI1‐expressing leukemia. (Cancer Sci 2008; 99: 1878–1883)