Targeting aberrant epigenetic condensates in myeloid malignancies
Hao Jiang
PhDUniversity of Virginia
Project Term: October 1, 2024 - September 30, 2027
Genetic changes of ASXL1 are very frequent in human blood cancers. We found that the altered forms of ASXL1 protein promote blood cancers through forming tiny liquid-like droplets in the cell. In this project, we aim to develop a method to specifically break these droplets to inhibit its activity in driving blood cancers.
Genetic changes in ASXL1 are very common in human blood cancers and always linked to adverse prognosis, relapse, and therapy resistance. These changes usually lead to a truncated form of the protein, which acquire aberrant activity in turning on the expression of many cancer-promoting genes. How the truncated ASXL1 gains the cancer-promoting activity is poorly understood, and no method is available to target these changed ASXL1 proteins for blood cancer therapy. We have shown that the truncated ASXL1 proteins have the ability to form tiny liquid-like droplets in cells, and this ability is crucial to promote blood cancer development. The region lost in ASXL1 truncation normally serves to control this ability, thus keeping the ASXL1 protein from forming these droplets.
Based on our findings of this new mechanism, we will develop a fundamentally new strategy to disrupt the formation of these droplets, thereby disrupting the activity of this protein in promoting blood cancer. To do this, we take advantage of the cell-intrinsic protein quality surveillance system composed of a type of very abundant and ubiquitous proteins called molecular chaperones. These chaperones normally function to ensure that cellular proteins adopt correct structure and do not become aggregated (that would be bad for the cells), and can also disperse protein droplets. We will develop a method to recognize and target the specific droplet-forming protein to the chaperones to disperse/disassemble the droplets and thus disrupt the function in supporting blood cancer.
If successfully accomplished, our proposed research will provide an entirely new avenue of treating blood cancer, by harnessing a cell-intrinsic protein surveillance system to disrupt the droplet formation of a key regulator. As our data suggest it works on a number of different proteins that forms droplets, we expect our strategy to be generally applicable for other droplet-forming proteins that drive other types of cancer. Therefore, this strategy can be developed to benefit all blood cancer patients and even other types of cancer.