Browsing by Author "Miao, Hongzhi"

Now showing 1 - 4 of 4
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    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 Medicine
    Homeobox 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.
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    Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity
    (Springer Nature, 2021-05-14) Rogawski, David S.; Deng, Jing; Li, Hao; Miao, Hongzhi; Borkin, Dmitry; Purohit, Trupta; Song, Jiho; Chase, Jennifer; Li, Shuangjiang; Ndoj, Juliano; Klossowski, Szymon; Kim, EunGi; Mao, Fengbiao; Zhou, Bo; Ropa, James; Krotoska, Marta Z.; Jin, Zhuang; Ernst, Patricia; Feng, Xiaomin; Huang, Gang; Nishioka, Kenichi; Kelly, Samantha; He, Miao; Wen, Bo; Sun, Duxin; Muntean, Andrew; Dou, Yali; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta; Microbiology and Immunology, School of Medicine
    ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.
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    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 Medicine
    Aberrant 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 overexpression
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    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 Medicine
    Chromosomal 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.