Targeting the transcription elongation machinery for treating MLL

Mixed Lineage Leukemia (MLL) is a type of cancer, which appears in cells of the blood, and is generally characterized with poor prognosis. Conventional therapy is ineffective, emphasizing the need for new treatments. MLL is characterized with genetic changes that lead to expression of novel fusion protein activators with oncogenesis potential. These disrupt the expression of genes that play a key role in development and maintenance of progenitor blood cells, thus may promote MLL malignancy. Our research aims to understand the molecular mechanisms that control the function of the transcription elongation machinery, positioning its proteins as targets for the development of drugs that will suppress the progression of MLL. We will focus on two important gene expression regulators termed Super Elongation Complex (SEC) and Positive Transcription Elongation Factor b (P-TEFb). Both gene activators act synergistically and enhance the activity of RNA Polymerase II and promote gene expression. Our preliminary results show that inhibition of the transcription activity of these two complexes or modulation of their expression disrupts growth and survival of leukemic cells. This proposal will establish the role of SEC and P-TEFb in the control of genes that are involved in development of hematopoietic stem cells, and will examine the efficacy of small molecules inhibitors that specifically inhibit their activity. It will elucidate the cross talk between gene expression, epigenetic regulators that combine and promote malignancy. Given the importance of gene expression in promoting MLL leukemia, we envision the knowledge gained from this study will have a wide impact on both the molecular mechanisms that drive MLL and on developing new therapeutic strategies to treat this disease.