Presenting Author:

Kelly Arcipowski, Ph.D.

Principal Investigator:

Panagiotis Ntziachristos, Ph.D.

Department:

Biochemistry and Molecular Genetics

Keywords:

leukemia, NOTCH1, deubiquitinase

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B11 - Basic Science

Targeting Deubiquitination in Acute Leukemia

Leukemia is a highly aggressive blood cancer affecting children and adults. The onset, progression, and outcome of this disease are associated with aberrant receptor activity, including Interleukin 7 or the JAK/STAT-associated cytokine receptors and pathways such as NOTCH1. We hypothesize that the process of oncogenic transformation in different leukemogenic pathways is driven by aberrant activity of oncogene-associated chromatin modifying partners. These enzymes create a chromatin environment unique to the malignant state and, therefore, disruption of critical oncogenic chromatin signatures would not likely affect healthy tissues. We have generated strong evidence for physical and functional interaction between oncogenes and deubiquitinase enzymes (members of the ubiquitin-specific proteases (USP) family) in T cell leukemia. Using state-of-the-art technologies, small molecule inhibitors, and genetic engineering of USPs in ALL cell lines, primary patient samples, and primagraft models of disease, we are able to show that a) USP activity is important for certain oncogenic pathways in leukemia; b) oncogenes and USP enzymes co-bind certain areas in the leukemia genome; and c) ubiquitination of histone H2B is a major epigenetic change affected by USP activity in leukemia and controls oncogenic transcriptional inititation and elongation. Finally, we were able to demonstrate that inhibition of USPs affects leukemia growth in vitro and in vivo. Ongoing and future studies include manipulation of USP levels in mouse models of leukemia, as well as combinatorial use of USP inhibitors with chemotherapeutic regiments in xenograft studies. Information gained from these studies will lend rationale towards the use of small molecule inhibitors against USP proteins in clinical trials for the treatment of leukemia.