I did my MD/PhD (MSTP, Immunology) and Hematology/Oncology fellowship training at the University of Pennsylvania. I then joined the Hematology/Oncology division at the University of Michigan in 2010. I spend 80% of my time running a laboratory focused on understanding the molecular mechanisms of leukemia oncogenesis using a combination of genetically engineered mouse models, human sample validation, transcription factor biology, proteomics, genomics, structural biology, and biochemistry. The other 20% of my time is spent teaching graduate and medical students, performing administrative duties (e.g. scientific advisory boards), and actively caring for patients with blood disorders.
Biography
Research Interests
While many transcription factors can cause cancer, they often have essential functions in other tissues. Thus, total inhibition of a transcription factor kills cancer cells, but damages normal cells, often resulting in unacceptable toxicities in patients. This conundrum is exemplified in the field studying cancers driven by the Notch transcription factor in which clinical trials involving more than 600 patients treated with Notch inhibitors developed intolerable on-target toxicities. Thus, the challenge for the field is to find ways to selectively target the oncogenic functions of transcription factors, but spare the essential normal functions.
To address this challenge, we showed that the PIAS-like coactivator Zmiz1 is a direct cofactor of Notch1 that selectively activates Notch-dependent superenhancers. Inactivation of Zmiz1 in mice with T-ALL causes tumor regression, but does not cause major toxicities, such as those linked to total Notch inhibition. Zmiz1 selectively and directly binds Notch1 through its TPR domain at a subset of Notch superenhancers, in particular Myc. We are now investigating other transcription factors and chromatin modifiers that promote context-dependent Notch activity. We employ a broad range of cutting edge techniques, including proteomics, genomics, drug screening, biochemistry, mouse models, and human sample manipulation. Our work raises the importance of cofactors that create the nuclear context at the chromatin that directs cancer cell type-specific functions of transcription factors. By targeting these factors, we might combat oncogenic transcription factors without major toxicities.
Publications
Chiang, M.Y.*, Shestova, O., Xu, L., Aster, J.C., Pear, W.S.Divergent effects of supraphysiological Notch signals on leukemia stem cells and hematopoietic stem cells. Blood. 121: 905-17, 2013. PMID: 23115273.
Rakowski, L.A., Garagiola, D.G.,Li, C.M., Decker, M., Caruso, S., Jones, M., Kuick, R., Cierpicki, T., Maillard, I., and Chiang, M.Y. Convergence of the ZMIZ1 and NOTCH1pathways at C-MYC in acute T lymphoblastic leukemias. Cancer Research. 73: 930-41, 2013. PMID: 23161489. PMCID: PMC3549029.
Pinnell NE and Chiang MY. Collaborating Pathways that Functionally Amplify NOTCH1 Signals in T-Cell Acute Lymphoblastic Leukemia. J Hematol Transfus. 2013. 1: 1004.
Pinnell N, Yan R, Cho H, Keeley T, Murai M, Liu Y, Serna Alarcon A, Qin, J., Wang, Q., Kuick R, Elenitoba-Johnson KSJ, Maillard I, Samuelson LC, Cierpicki T, Chiang MY. The PIAS-like coactivator Zmiz1 is a direct and selective cofactor of Notch1 in T-cell development and leukemia. Immunity. 43: 870-993, 2015. (Previewed by Helbig, C. and Amsen, D. Notch Signaling: Piercing a Harness of Simplicity, Immunity. 43: 881-883, 2015).
Chiang MY, Wang Q, Gormley AC, Stein, SJ, Xu L, Shestova O, Aster JC, Pear WS. High selective pressure for Notch1 mutations that induce Myc in T cell acute lymphoblastic leukemia. Blood. 128: 2229-2240. 2016. PMID 27970423.
Chiang MY, Radojcic V, Maillard, I. Oncogenic Notch signaling in T and B cell lymphoproliferative disorders. Curr Opin Hematol. 2016. PMID: 27135981. PMCID: PMC4962559
McCarter A, Wang Q, Chiang MY. Notch in Leukemia. Molecular Mechanisms of Notch Signaling. 2018. (In Press.)