Histone modifications and aberrant transcription in AML/MDS

In the past few years our vision of chromatin has changed dramatically. Epigenetic processes including covalent DNA modifications, covalent histone modifications and histone relocation influence chromatin structure and thereby regulate gene expression and DNA methylation, replication, recombination and repair. Histone modifications are believed to play a crucial role in the establishment and maintenance of the chromatin structure. Especially residues in the N-terminal tails of histones H3 and H4 and the N-terminal and C-terminal tails of histones H2A and H2B have been found as targets of various modifications like acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation. Recent findings have shown that certain modifications marks produce precise regulatory effects. Combinations of modifications result in an epigenetic code that determines specific transcriptional states. Fidelity in the preservation of tissue-specific gene expression is crucial for nearly all aspects of normal growth and development of a multicellular organism. Dysregulation or disruption of this system of transcriptional memory often causes severe growth defects and contributes to diseased states, facilitating tumor progression and metastasis. This project contributes to efforts to decipher the molecular basis of the myeloid diseases AML and MDS. The chromosomal translocations found in AML and MDS most commonly rearrange genes encoding transcription factors and other transcriptional regulatory proteins. These genetic lesions generate transcriptional repressors that appear to interfere with the expression of genes required for normal hematopoietic differentiation. The process of repression involves a series of key protein-protein interactions that results in histone modifications, DNA methylation and other cellular events. I want to identify protein complexes that mediate aberrant transcription in malignant cells, characterizing their associated biochemical activities, defining the structural basis for their interactions, and identifying small molecules that can alter their function. I will be especially focusing on the polycomb group (PcG) and trithorax group (TrxG) proteins, which normally oppose each other`s function during development. Both classes of proteins are altered in hematologic malignancies and are assumed to play a crucial role during the evolvement of malignancies. I will utilize proteomics and detailed biochemical and structure- function analyses to both define how these transcriptional regulatory complexes are deranged in AML and MDS and learn how to correct or overcome these abnormalities. At present patients with these diseases are treated with supportive care or stem cell transplantation although the prognosis remains dismal with median survival rates. Investigation of the molecular basis of AML and MDS will help to develop therapies that can correct these underlying molecular defects.