Epigenetic signaling and rational therapy of acute myeloid leukemia
Extensive genome sequencing has produced a nearly complete compendium of genetic aberrations in both pediatric and adult acute myeloid leukemias. In spite of this, the molecular mechanisms of aberrant cell survival and salient features of disease such as therapy resistance remain elusive.
We have adapted recently developed high-resolution mass spectrometers for ultra-sensitive analyses of aberrant signaling and gene expression of cancer cells. Using both discovery and mechanism-based paradigms, we generate quantitative models of cellular signaling and its control of gene expression to explain fundamental behaviors of leukemia cells, including aberrant cell survival, self-renewal, and resistance and adaptation to cancer therapy. We pursue this fundamental question: Do leukemia cells use normal molecular mechanics out of place and time, or do they depend on inherently aberrant molecular structures?
In particular, we are investigating the mechanisms by which kinase signaling controls pioneer hematopoietic transcription factors, such as MEF2C and MYB, to induce and sustain leukemogenesis. In particular, we recently discovered that kinase-dependent dysregulation of transcription factor control is a determinant of therapy response in AML, and that peptidomimetic blockade of transcriptional coactivation can be used for its therapeutic targeting and discovery of fundamental mechanisms of cancer gene control.
This work aims to define specific molecular aberrations of signaling cascades and gene expression control complexes that lead to pathogenic cell fate specification and therapy resistance. Using protein engineering, biochemical and cell biological approaches, we generate molecular probes to perturb signaling and transcription factor complexes. Using genetically-engineered and primary human xenograft leukemia mouse models, we determine their anti-leukemogenic activities in structure-function studies, as a prelude to their potential therapeutic targeting in future clinical trials.