Molecular Mechanisms Driving Acute Myeloid Leukemia

A longstanding interest in the laboratory has been to understand the molecular aspects of how mutations in the hematopoietic stem cells drive acute myeloid leukemia (AML). We aim to develop novel therapeutics that can be brought to the clinic.

With focus on the leukemia fusion protein CBFß-SMMHC, which results from an inversion in chromosome 16, we have established that the fusion protein drives leukemia development, and that the leukemia stem cells remain dependent on its function to expand.

Functionally, we have established that expression of the CBFß-SMMHC in hematopoietic stem cells creates a preleukemic progenitors that lead to AML in cooperation with other mutations (Castilla et al., Cell 1996, Nat Genet 1999). These mutations enhance leukemic stem cells activity in mice (Kuo et al., Cancer Cell 2006; Xue et al., Blood 2014). We have shown that CBFß-SMMHC is critical for maintenance of AML by regulating expression of oncoproteins such as MYC, and its repression triggers apoptosis (Pulikkan et al., Cell 2018).

Mechanistically, we have combined genetic, gene editing, genomic and pharmacologic approaches to demonstrate that CBFß-SMMHC blocks RUNX1 function at specific enhancer and promoter regions, repressing expression of myeloid and lymphoid factors (Kuo et al., Cancer Cell 2006; Blood 2008).

We continue utilizing state-of-the art approaches to elucidate how founding mutations direct leukemia development, with the goal of developing clinically relevant therapies for AML.