Acute leukemia, including acute myeloid (AML) and lymphoid leukemia (ALL), is the most common (1 out of 3) cancer in children and adolescents. Particularly, leukemia caused by chromosome translocations involving mixed lineage leukemia (MLL) gene accounts for ~75% of leukemia in infants and ~10% in children/adults with a poor prognosis. Compared to other pediatric ALL with a 5-year survival of ~90%, that for MLL-rearranged ALL is only ~40%, and for very young infants, the survival is even less than 20%. MLL-rearranged AML patients have similarly poor clinical outcomes (5-year survivals of ~45%) to other AMLs.

Current treatments are chemo-drugs, which kill all rapidly proliferating cells inclu...

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Acute leukemia, including acute myeloid (AML) and lymphoid leukemia (ALL), is the most common (1 out of 3) cancer in children and adolescents. Particularly, leukemia caused by chromosome translocations involving mixed lineage leukemia (MLL) gene accounts for ~75% of leukemia in infants and ~10% in children/adults with a poor prognosis. Compared to other pediatric ALL with a 5-year survival of ~90%, that for MLL-rearranged ALL is only ~40%, and for very young infants, the survival is even less than 20%. MLL-rearranged AML patients have similarly poor clinical outcomes (5-year survivals of ~45%) to other AMLs.

Current treatments are chemo-drugs, which kill all rapidly proliferating cells including normal stem cells in bone marrow and other organs. This causes severe toxicities, side effects, and secondary cancer due to mutagenesis. There is therefore a pressing need to find less toxic drugs targeting MLL-oncogene that drives the malignancy. MLL-oncogene consists of MLL fused with another gene. AF9 (~30%) and AF4 (35%) are the most frequent fusion partners of MLL. These proteins, together with DOT1L (a known drug target for the leukemia), associate with each other and constitute the so-called super elongation complex, which causes malignant gene expression in leukemia. Previous studies show the protein-protein interactions between AF9 and AF4 or DOT1L is critical to MLL-leukemia, but is dispensable in normal cells.

This project aims to find and develop the first small-molecule inhibitors that disrupt the AF9-AF4/DOT1L interaction, which could be novel therapeutics for MLL-rearranged leukemia with a low toxicity. In our preliminary studies, several drug-like inhibitors of AF9/ENL have been identified and showed on-target anti-leukemia activity. We propose to use medicinal chemistry and biological activity testing to find more potent compounds. Success of the project could identify first-in-class drug candidates for MLL-rearranged leukemia.

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