Development is controlled by the timely expression and function of transcription factors that regulate gene expression and determine cell fate and function. Leukemia is often driven by chromosomal translocations that result in the production of novel transcription factors, produced by the abnormal fusion of two separate gene products. In acute myelogenous leukemia (AML), the most common such fusion is the t(8;21)-derived AML1- ETO (AE), which drives leukemia by co-opting additional normal cellular transcription factors that are critical for blood stem cell self-renewal and proliferation, thereby trapping the cells in a proliferative immature state that is the basis of leukemia. It has proved difficult to inhibit transcription factor functions pharmacologically, leading us to look for essential AE cofactors that are more tractable drug targets. Our goal is to combine different experimental approaches to decipher the mechanisms of gene regulation in AML, including identification of new players in different hierarchies of regulation that will reveal new opportunities for therapeutics. In recent studies, we identified an AE-associated transcription factor/cofactor complex (AETFC) and pinpointed a novel interaction surface between AE and E proteins that is critical for AETFC function and leukemogenesis. Most importantly, we showed in mouse models that disruption of this interaction severely reduces AE oncogenicity. In addition, we also identified JMJD1C as a novel coactivator for AETFC. JMJD1C is of special interest in that it is a histone 3 lysine 9 demethylase with an enzymatic activity pocket that can ultimately be targeted by small molecules. Notably, our studies have also shown that JMJD1C is critical for survival not only of t(8;21) cells, but also several different types of AML cells, suggesting its potential role as a general coactivator for shared key transcriptional factors, providing another opportunity for therapeutic development through inhibiting TF-cofactor interaction. Based on our published work and preliminary studies, we propose to continue and expand our original proposed studies in the following aspects. First, we will systematically dissect newly indicated sub-complexes of AETFC and determine how they guide coactivators and corepressors to important target genes (Aim 1). Second, we will detail the molecular mechanisms underlying the pan-JMJD1C dependency of different types of leukemia (Aim 2). We will employ several complementary approaches that include: (i) cell-free systems reconstituted with purified factors and DNA/chromatin templates, to reveal direct cofactor effects and mechanisms; (ii) leukemic cell-based assays to monitor dynamic changes upon introduction of mutants or deletion of components of TF networks; (iii) genome-wide analyses that include ATAC-seq, ChIP-seq and RNA-seq. Third, we will develop/employ new mouse models for t(8;21) leukemia to validate newly identified players/interactions in AML (Aim 3). Altogether, the proposed approaches will unearth additional mechanistic insights and protein/enzyme targets that will provide novel therapeutic opportunities in AML.

Public Health Relevance

Hematopoiesis is controlled by the differential expression of key transcription factors that act cooperatively to maintain a well-orchestrated balance of hematopoietic stem cell self-renewal and differentiation. The proposed studies will continue to provide novel insights in how leukemogenic transcription factors, together with interacting cofactors, act cooperatively to define cell identity and divert normal hematopoietic differentiation programs into leukemic programs. Related mechanistic studies, in turn, will have important implications for possible therapeutic interventions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Jhappan, Chamelli
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Rockefeller University
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New York
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Zhu, Nan; Chen, Mo; Eng, Rowena et al. (2016) MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 126:997-1011
Li, Yuanyuan; Sabari, Benjamin R; Panchenko, Tatyana et al. (2016) Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol Cell 62:181-193
Chen, Mo; Zhu, Nan; Liu, Xiaochuan et al. (2015) JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. Genes Dev 29:2123-39
Geng, Huimin; Hurtz, Christian; Lenz, Kyle B et al. (2015) Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer Cell 27:409-25
Chen, Wei-Yi; Zhang, Jinsong; Geng, Huimin et al. (2013) A TAF4 coactivator function for E proteins that involves enhanced TFIID binding. Genes Dev 27:1596-609
Sun, Xiao-Jian; Wang, Zhanxin; Wang, Lan et al. (2013) A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 500:93-7