G Greg Wang
Duke University, NC·Biochemistry
Cancer often begins when chromosomes break and rejoin in the wrong order, fusing two genes into one hybrid protein that behaves in ways neither original did. Both projects here ask how such fusion proteins and chromatin regulators, factors that control how DNA is packaged and which genes are switched on, drive aggressive leukemias, and how those mechanisms can be drugged.
- Fields
Biochemistry
Genetics
Pharmacology
- Topics
leukemia
NUP98 rearrangement
MLL1 rearrangement
- Grants
- 2 known grants, through Jun 2027
What they work on
- Characterize how the previously unstudied intrinsically disordered region of the RNA-binding protein MSI2 drives liquid-liquid phase separation, using purified proteins in vitro and in living cells.
- Define how disordered regions and phase separation control genome-wide binding, target gene expression and leukemic transformation by NUP98-PHD, MSI2-HOXA9 and NUP98-HOXA9 fusions, using primary human hematopoietic stem and progenitor cells and mouse models.
- Map three-dimensional chromatin structure changes caused by NUP98 rearrangements and MSI2-HOXA9 in disease-relevant cells, and test whether CTCF-independent, phase-separation-dependent DNA loops sustain oncogene activation using a CRISPR/dCas9 fused to a disordered region.
- Characterize the non-canonical oncogenic function of EZH2, in which it binds c-MYC and activates oncogenes such as Cyclin E1, in MLL1-rearranged leukemia cells, in contrast to its classical gene-silencing role in Polycomb Repressive Complex 2.
- Determine whether EZH2 PROTAC degraders such as MS177, which tag the protein for cellular destruction, suppress both the Polycomb-dependent and c-MYC-associated activities of EZH2 better than enzyme inhibitors.
- Test therapeutic effect of EZH2 degraders in multiple MLL1-rearranged leukemia models, including human and mouse cancer cells and patient-derived xenografts, and optimize the leads into a drug candidate.
More about the research
One project focuses on a physical phenomenon, the ability of certain floppy protein regions to condense into droplet-like compartments inside the nucleus; the other focuses on an enzyme, EZH2, that turns out to do more than its textbook job. Both use human and mouse leukemia models and aim at new treatment strategies for patients whose outcomes are currently poor.
Why it matters
Patients with leukemias carrying NUP98 or MLL1 gene rearrangements have particularly poor outcomes and limited treatment options. Understanding how disordered protein regions and phase separation rewire three-dimensional genome organization could reveal a new class of targets in cancers driven by such proteins, while the EZH2 degrader work aims to validate a therapeutic strategy superior to existing enzyme inhibitors and to deliver an optimized drug candidate for MLL1-rearranged leukemia.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Danfeng Cai
Johns Hopkins University, MD·Biochemistry
Determine how RNA binding through RNA-recognition motifs, together with coiled-coil domains, drives the NONO-TFE3 and SFPQ-TFE3 fusion oncoproteins to form condensates in the nucleus.
Yali Dou
University of Southern California, CA·Biochemistry
Define how the histone H3 K4 methyltransferase MLL1 (KMT2A) promotes cancer development through its canonical, transcription-dependent activity within its multi-subunit complex shared with other KMT2 family enzymes.
Shaomeng Wang
University of Michigan, MI·Pharmacology
Optimize orally active small-molecule degraders that destroy both CBP and p300, paired histone acetyltransferases that switch on gene programs, and test them as a therapy for advanced, castration-resistant prostate cancer in mouse models.
The school
Duke University: 61 labs on PI Pages, $1.6B a year on research, 417 research doctorates a year.
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