Jay L. Hess
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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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Item Medical School Without Walls: 50 Years of Regional Campuses at Indiana University School of Medicine(Wolters Kluwer, 2022-12) Wallach, Paul M.; Birnbaum, Deborah R.; Ryan, Elizabeth R.; Pieczko, Brandon T.; Hess, Jay L.The history of Indiana University School of Medicine (IUSM) dates to 1871, when Indiana Medical College entered into an affiliation with Indiana University in Bloomington to offer medical education. In 1971, the Indiana General Assembly passed a bill to create and fund a distributed model for medical education for which IUSM was responsible, an innovative approach to implementing a statewide medical education program. IUSM became one of the first U.S. medical schools to implement what is today known as a regional medical campus model. This regional medical campus system has permitted IUSM to expand enrollment based on national and local concerns about physician shortages, increase access to care locally, support expansion of graduate medical education, and provide opportunities for research and scholarship by faculty and students statewide. This effort was made possible by partnerships with other universities and health care systems across the state and the support of local community and state leaders. The model is a forward-thinking and cost-effective way to educate physicians for service in the state of Indiana and is applicable to others. This article highlights milestones in IUSM’s 50-year history of regional medical education, describes the development of the regional medical campus model, recognizes significant achievements over the years, shares lessons learned, and discusses considerations for the future of medical education.Item HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis(Elsevier, 2018-10-08) Sun, Yuqing; Zhou, Bo; Mao, Fengbiao; Xu, Jing; Miao, Hongzhi; Zou, Zhenhua; Khoa, Le Tran Phuc; Jang, Younghoon; Cai, Sheng; Witkin, Matthew; Koche, Richard; Ge, Kai; Dressler, Gregory; Levine, Ross L.; Armstrong, Scott A.; Dou, Yali; Hess, Jay L.; Pathology and Laboratory Medicine, School of MedicineAberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpressionItem 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 MedicineC/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.Item The protective role of DOT1L in UV-induced melanomagenesis(Nature Publishing Group, 2018-01-17) Zhu, Bo; Chen, Shuyang; Wang, Hongshen; Yin, Chengqian; Han, Changpeng; Peng, Cong; Liu, Zhaoqian; Wan, Lixin; Zhang, Zhang; Zhang, Jie; Lian, Christine G.; Ma, Peilin; Xu, Zhi-xiang; Prince, Sharon; Wang, Tao; Gao, Xiumei; Shi, Yujiang; Liu, Dali; Liu, Min; Wei, Wenyi; Wei, Zhi; Pan, Jingxuan; Wang, Yongjun; Xuan, Zhenyu; Hess, Jay L.; Hayward, Nicholas K.; Goding, Colin R.; Chen, Xiang; Zhou, Jun; Cui, Rutao; Pathology and Laboratory Medicine, School of MedicineThe DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.Item A new target for differentiation therapy in AML(Springer Nature, 2017-01) Ma, Peilin; Song, Weihua; Hess, Jay L.; Pathology and Laboratory Medicine, School of MedicineDespite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets.Item Deregulation of the HOXA9/MEIS1 Axis in Acute Leukemia(Wolters Kluwer, 2016-07) Collins, Cailin T.; Hess, Jay L.; Office of Dean, School of MedicinePurpose of review HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, where its over expression is strongly correlated with poor prognosis. This review highlights recent advances in the understanding of genetic alterations leading to deregulation of HOXA9 and the downstream mechanisms of HOXA9-mediated transformation. Recent findings A variety of genetic alterations including MLL-translocations, NUP98-fusions, NPM1 mutations, CDX deregulation, and MOZ-fusions lead to high level HOXA9 expression in acute leukemias. The mechanisms resulting in HOXA9 over expression are beginning to be defined and represent attractive therapeutic targets. Small molecules targeting MLL-fusion protein complex members, such as DOT1L and menin, have shown promising results in animal models, and a DOT1L inhibitor is currently being tested in clinical trials. Essential HOXA9 cofactors and collaborators are also being identified, including transcription factors PU.1 and C/EBPα, which are required for HOXA9-driven leukemia. HOXA9 targets including IGF1, CDX4, INK4A/INK4B/ARF, mir-21 and mir-196b and many others provide another avenue for potential drug development. Summary HOXA9 deregulation underlies a large subset of aggressive acute leukemias. Understanding the mechanisms regulating the expression and activity of HOXA9, along with its critical downstream targets, shows promise for the development of more selective and effective leukemia therapies.Item Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo(Elsevier, 2015-04-13) Borkin, Dmitry; He, Shihan; Miao, Hongzhi; Kempinska, Katarzyna; Pollock, Jonathan; Chase, Jennifer; Purohit, Trupta; Malik, Bhavna; Zhao, Ting; Wang, Jingya; Wen, Bo; Zong, Hongliang; Jones, Morgan; Danet-Desnoyers, Gwenn; Guzman, Monica L.; Talpaz, Moshe; Bixby, Dale L.; Sun, Duxin; Hess, Jay L.; Muntean, Andrew G.; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta; Dean, IU School of MedicineChromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.Item Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia(Elsevier, 2014-01-23) Cao, Fang; Townsend, Elizabeth C.; Karatas, Hacer; Xu, Jing; Li, Li; Lee, Shirley; Liu, Liu; Chen, Yong; Ouillette, Peter; Zhu, Jidong; Hess, Jay L.; Atadja, Peter; Lei, Ming; Qin, Zhaohui; Malek, Sami; Wang, Shaomeng; Dou, Yali; IU School of MedicineHere we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.Item C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis(PNAS, 2014-07-08) Collins, Cailin; Wang, Jingya; Miao, Hongzhi; Bronstein, Joel; Nawer, Humaira; Xu, Tao; Figueroa, Maria; Muntean, Andrew G.; Hess, Jay L.; Department of Medicine, IU School of MedicineHomeobox A9 (HOXA9) is a homeodomain-containing transcription factor that plays a key role in hematopoietic stem cell expansion and is commonly deregulated in human acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia (AML) lead to overexpression of HOXA9, almost always in association with overexpression of its cofactor meis homeobox 1 (MEIS1) . A wide range of data suggests that HOXA9 and MEIS1 play a synergistic causative role in AML, although the molecular mechanisms leading to transformation by HOXA9 and MEIS1 remain elusive. In this study, we identify CCAAT/enhancer binding protein alpha (C/EBPα) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBPα is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBPα greatly improves survival in both primary and secondary murine models of Hoxa9/Meis1-induced leukemia. Over 50% of Hoxa9 genome-wide binding sites are cobound by C/EBPα, which coregulates a number of downstream target genes involved in the regulation of cell proliferation and differentiation. Finally, we show that Hoxa9 represses the locus of the cyclin-dependent kinase inhibitors Cdkn2a/b in concert with C/EBPα to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBPα in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis.