Mark Y Chiang, MD, PhD

For more than 20 years I have investigated the transcriptional pathways that promote normal and malignant lymphoid development. I established collaborations with a T-cell transcription factor biologist (J. Douglas Engel), bioinformatician/biostatisticians (Arvind Rao, Brian Magnuson, and Karan Bedi), an RNA biologist (Mats Ljungman), a structural biologist (Tomasz Cierpicki), a medicinal chemist (Jolanta Grembecka), a Notch biologist (Linda Samuelson), an enhancer expert (Russell Ryan), and a Phase I trials expert (Moshe Talpaz). My goal is to understand how Notch1-collaborating transcription factors (“Notch cofactors”) co-bind Notch-occupied regulatory elements to create the T-cell chromatin context that directs Notch to execute its functions during T-cell development and leukemogenesis. My vision is that if cell-specific Notch cofactors are hijacked to drive Notch-induced T-ALL, then inhibiting them might oppose Notch signals in cancer and circumvent the toxicities of systemic pan-Notch inhibition. To this end, we reported the discovery of a direct and context-dependent Notch1 cofactor called Zmiz1. Zmiz1-regulated complexes promote T-cell Notch functions, but not essential Notch functions. More recently, we show that ETS1 is the top-ranked Notch collaborating transcription factor in T-ALL. In contrast to other transcription factors, ETS is the #1 most frequent and statistically significant motif (after RBPJ) at Notch/RBPJ-bound elements. In contrast to other factors, ETS1 physically binds and recruits Notch to chromatin as well as CDC73, the scaffold component of the polymerase-associated factor complex (PAF1C), to activate response elements. One of these elements is a previously unrecognized stem cell superenhancer that we believe is the primary enhancer that induces the MYB oncogene in T-ALL cells. We nicknamed this element “E-Me” for Ets1-dependent MYB enhancer. This enhancer is essential for hematopoietic stem cell self-renewal, early T-cell precursor maintenance, and T-ALL proliferation but is not essential for health. Our impact is that we provide the basic science foundation to exploit transcription factors and regulatory elements to promote thymic regeneration after cytoreduction and disable Notch-driven oncogenic signals without the intolerable toxicities of pan-Notch inhibitors seen in clinical trials.

1. T-cell Acute Lymphoblastic Leukemia
2. Early T-cell Precursor Acute Lymphoblastic Leukemia
3. Early T-cell development
4. Thymic regeneration after cytoreductive therapy
5. Notch signaling
6. Oncogenic transcription factors and cofactors
7. Transcriptional networks of essential regulatory elements
8. Protein-protein interactions
9. Leukemia stem cells
10. Mouse modeling of hematological malignancies