Linker Histone Mutations Mediate Lymphomagenesis Through a Novel Chromatin Mechanism
Abstract
My career goal is to become a tenure-track faculty leading high-impact cancer research at a medical school university. I hope to make a meaningful and impactful contribution to the treatment of human disease by studying the underlying molecular mechanisms and linking them to the clinical translation of novel therapies or the improvement of existing treatments. The Horizon Award will advance my career in lymphoma research, because it will provide me the funding opportunity to test a well-constructed hypothesis and answer how linker histone deficiency affects early onset of lymphomagenesis. It will provide me with the opportunity to travel to scientific conferences to gain new ideas and learn from experts around the country. This research will advance the lymphoma field because it will identify the biological impact of highly recurrent mutations and guide the development of rational combination therapies in patients with the greatest need. The researcher development plan supports me in attaining these goals because my plan will provide me maximum mentorship with a world-renowned faculty and access to the expertise of investigators based at Weill Cornell Medicine. I will take advantage of lectures and seminars to enrich my knowledge of chromatin biology, pathogenic histone mutations, and genome-wide analysis to utilize novel technologies and experimental study designs. Lymphoma is a form of cancer of immune cells (B cells) that affects the immune system. Follicular lymphomas (FL) are the second most common subtype of non-Hodgkin lymphoma. While clinically characterized as slow progression, FL is considered incurable, and roughly half of all FL patients eventually progress into a more aggressive lymphoma, with very poor prognosis. Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, curable with combination therapy (R-CHOP) in over 60% of patients. The remainder develop recurrent or progressive disease that is often fatal. These tumors are currently thought to arise from antigen-exposed B cells that transit through the germinal center (GC) reaction. Aspects of the GC environment such as faster growth and high tolerance to changes in the genetic material make B-cells conducive to malignancy. Any alterations in the tightly controlled reaction can cause cells to become unresponsive to signals cueing to exit this program. B cells thus become "lockdown" in this program of high growth and fail to die when instructed to, collecting in the lymph nodes and forming tumors. Recently, multiple studies analyzing the genomes of DLBCL and FL patients pointed out to a highly co-occuring mutation in the genes called HIST1H1C and HIST1H1E. Very little is known about the mechanism of action of H1 genes and even less is known about the biochemical and biological consequence of their mutations. The proposed research has significant applicability because it aims to unravel a novel mechanism of malignant transformation of B-cells different from what is known so far about the disease. If successful, this work can provide direct clinical insight to a certain group of patients with previously undescribed genetic background. Specifically, recently reported clinical observations of lymphomas with H1 mutations showing resistance after targeting the lymphoma-causing mutation EZH2 suggests a direct path for applying our discoveries to unravel new mechanisms of response and predict refractory to treatment lymphomas in the clinic. Our work will benefit military personnel because lymphoma incidences are increased in active duty military personnel, likely due to previous chemotherapy treatments for other malignancies increasing risk to develop non-Hodgkin lymphoma. The proposed project will illuminate distinct basic cellular mechanisms that can be used to classify disease and predict clinical outcome for Veterans, active duty Service members, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910216
Entities
People
- Nevin Yusufova
Organizations
- United States Army
- Weill Cornell Medicine