Award Recipient 
MICRTP Award 2016

Transcriptomic and epigenetic reprogramming by a leukemic fusion protein

September 2016 

Epigenetic dysregulation is important in leukemia development. How this occurs through genome-wide chromatin reorganization and modifications remains largely unclear.

Our lab has been focused on two paralogous histone acetyltransferases called MOZ and MORF. Their genes have recently been identified as two high-ranking targets amplified in different types of cancer. MOZ gene was first identified as a fusion partner which is associated with acute myeloid leukemia. One form of MOZ rearrangement creates the fusion protein MOZ-TIF2, which is composed of the N-terminal part of MOZ and the C-terminal part of the transcriptional coactivator TIF2. MOZ-TIF2 is leukemic and confers self-renewal to committed hematopoietic progenitors. One common feature that MOZ-TIF2 shares with other leukemic MOZ and MORF proteins is retention of the MYST domain, which confers acetyltransferase activity and interacts with a novel epigenetic regulator called BRPF1. BRPF1 may stimulate acetyltransferase activity, restrict substrate specificity and potentiate transcriptional ability of MOZ-TIF2. As an example, we have recently shown that Brpf1 is important for hematopoietic stem cell development, affects many histone acetylation sites and alters expression of genes related to HSC.

The hypothesis is that leukemic proteins such as MOZ-TIF2 reprogram chromatin organization and alter gene expression.  Based on this hypothesis, multiple approaches such as lentivirus delivery, bone marrow transplantation, RNA-seq and ATAC-seq techniques will be used to determine how MOZ-TIF2 alters gene expression as well as affect chromatin organization.

The dissection of mechanism on how MOZ-TIF2 alters gene expression and reprograms chromatin organization will deepen our understanding of acute myeloid leukemia and provide insight for leukemia treatment.

Lin Li
Division of Experimental Medicine, McGill University
PhD candidate,  Laboratory of Xiang Jiao Yang