Jay L. Hess

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https://hdl.handle.net/1805/11710

Identifying and Treating Leukemia

Jay L. Hess has worked in early stage drug discovery in academia and in establishing sequencing-based diagnostics to improve care for cancer patients. A board-certified Hematopathologist and author of more than 100 scientific papers and book chapters, Dr. Hess is considered one of the nation’s leaders in the epigenetics of leukemia. He continues to run an active NIH-funded research laboratory.

Dr. Hess became the 10th Dean of the IU School of Medicine (IUSM) and Vice President for University Clinical Affairs at Indiana University on September 1st, 2013. He joined IUSM after eight years at the University of Michigan, where he advanced the causes of translational research, pathology informatics and sequencing-based diagnostics.

While at Michigan, Dr. Hess helped establish the Michigan Center for Translational Pathology, created one of the first pathology informatics divisions in the nation and led the University of Michigan Health Care System strategy implementation in personalized medicine. In 2012, he co-founded and chaired the board of directors for Paradigm, a sequencing-based not-for-profit diagnostics company that provides next generation sequencing and data analysis to improve care for cancer patients.

Dr. Hess’s work to address bottlenecks in clinical translation of more targeted and effective therapies is another example of how IUPUI’s faculty members are TRANSLATING their RESEARCH INTO PRACTICE.

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Browsing Jay L. Hess by Subject "Cebpa gene expression"

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    HoxA9 binds and represses the Cebpa +8 kb enhancer
    (PLOS, 2019-05-23) Peng, Lei; Guo, Hong; Ma, Peilin; Sun, Yuqing; Dennison, Lauren; Aplan, Peter D.; Hess, Jay L.; Friedman, Alan D.; Pathology and Laboratory Medicine, School of Medicine
    C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9.