Role of ID2 in mature T-cell lymphoma
Anouchka Laurent
PhDColumbia University Irving Medical Center
Project Term: July 1, 2024 - June 30, 2026
Overexpression of ID2 is a recurrent event in mature T-cell lymphoma (TCL), and its significance is yet to be established. We will use a multidisciplinary approach combining epigenetic, transcriptomic, and proteomic analysis in human and murine models to identify the mechanisms leading to ID2 overexpression and their effect on T-cell transformation. Our goal is to define the role of ID2 in lymphomagenesis and determine its potential as a novel therapeutic target in TCL.
Mature T-cell lymphoma (TCL) is a heterogenous group of diseases that result from the malignant transformation of T-cell due to alterations in the genome. Among mature T-cell lymphoma, most of the Peripheral T-cell lymphomas (PTCL) and Cutaneous T-cell lymphomas subgroups are associated with poor response to traditional chemotherapy approaches and dismal prognosis. These suboptimal clinical results underscore the need, as well as our commitment, to developing more effective and less toxic drugs. We recently identified that a gene called ID2 is frequently altered in T-cell lymphoma. Interestingly, we found that ID2 is expressed the highest in T-cell lymphoma compared to any other type of cell line in the Cancer Cell Encyclopedia, pointing to an important role of ID2 in T-cell lymphoma. Indeed, our preliminary data showed that expression of ID2 facilitates tumor growth and improves survival in malignant lymphoma cells. We also identified that specific changes in the chromatin in lymphoma cells might be associated with the dysregulation of ID2. Our hypothesis is that these changes in chromatin marks are associated with malignant transformation, regulate processes that are important for the lymphoma cells and can potentially be targeted with new drugs. Thus, our goal is (i) understand how ID2 is regulated in lymphoma; and (ii) identify if novel ID2 inhibitors that could potentially induce lymphoma cell death.
Our project demonstrates fundamental innovation by using genetically manipulated animal models specifically developed in our laboratory and relevant experimental approaches and brings together a unique team of researchers with ample expertise in lymphoma, ID2 proteins, and preclinical testing of novel drugs. Importantly, our preliminary drug experiments using a specific inhibitor of ID proteins, called AGX51, have already shown promising results in cellular models of human and mouse T-cell lymphoma. We anticipate that upon successful completion of our proposal, we will understand how ID2 is regulated, how it participates in transformation, and whether it constitutes an actionable therapeutic target to improve the treatment of TCL patients. Our future goal would be to translate our findings back to clinical application and rationally design a clinical trial using ID2 inhibitors, alone or in combination with current targeted therapies, for his devastating disease.