Targeting the Core Binding Factor tumor suppressor in MLL-fusion AML

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DESCRIPTION (provided by applicant): RUNX1 is considered a beneficial tumor suppressor in myeloid neoplasms. Inhibition of RUNX1 function has been implicated as an important mechanistic event in the development of core-binding factor-(CBF)-leukemia and MLL-fusion leukemia. Inactivating RUNX1 mutations are frequently found in patients with acute myeloid leukemia (AML). However, RUNX1 mutation is usually heterozygous, complete loss of RUNX1 in AML is rare and no somatic RUNX1 mutation have been found in AMLs with common fusion proteins, such as CBF- and MLL-fusion leukemias. These data raise the possibility that a certain (low) level of RUNX1 activity is required for survival and growth of AML. We have developed human models for AML by transducing leukemogenic fusion proteins into human cord blood CD34+ cells. MLL-AF9-expressing cord blood cells cause human leukemia when transplanted into immunodeficient mice. We recently found that these AML cells critically depend on RUNX1 activity for sustained growth and survival, indicating that RUNX1 is a promising therapeutic strategy for AML. We will clarify molecular mechanisms underlying RUNX1-mediated survival/growth of AML cells and translate these findings into the clinic, using a novel RUNX1 inhibitor in murine xenograft models of human AML. This study will provide a proof of principle to the proposed strategy, and will serve as useful preclinical preliminary data for clinical application.