Identifying therapeutic targets of the Hox-Meis network that regulate leukemia stem cell fate.
Canadian Institutes of Health Research
- Grant type: CIHR Fellowship
- Years: 2013/14 to 2015/16
- Total Funding: $88,556
Yeh, Jonathan R
University of Montreal
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Acute myeloid leukemia (AML) is diagnosed annually in ~1,200 patients in Canada. Treatment for this disease has not changed significantly over the last 30 years and the overall survival of AML patients remains close to 20%. Unfortunately, most AML patients relapse within 3 years of diagnosis and of these only 11% will survive past 5 years. One major reason for relapse is the persistence of a leukemia stem cell (LSC) population following therapy. LSCs are defined by their ability to self-renew and continually repopulate leukemic cells. However, the networks governing self-renewal are unknown. Previously, our group showed that HOXA9 and MEIS1 genes cause leukemia in mice and likely in humans. Deregulation of HOX, MEIS, and PBX genes represents one of the most frequent molecular anomalies in human leukemia (deregulated in approximately 50% of acute leukemias) and are associated with adverse prognosis. HOX proteins and co-factors (MEIS-PBX) are potent nuclear oncogenes. Over the years, our group has characterized several components involved in HOX-MEIS-PBX leukemia and paved the way to identify, test, and further develop small molecules and therapeutic targets for this disease. In this application, I hypothesize that HOX-MEIS-PBX is an important network that regulates human LSCs. Understanding of this network may allow for LSC targeting and treatment of intermediate-risk AML at its basis, thereby avoiding relapse. Over the course of two separate, yet integrated, aims I propose to characterize the nature (Aim 1) and test the functional importance (Aim 2) of the HOX-MEIS-PBX complex in human LSCs and leukemias. The proposed studies will characterize therapeutic targets both upstream and downstream of HOX-MEIS-PBX. Collectively these results will provide a comprehensive characterization and therapeutic validation of the HOX-MEIS-PBX transforming network and may facilitate targeting and manipulation of LSCs in human acute leukemias.