Epigenetic Plasticity in Pediatric Pre-B-Cell Acute Lymphoblastic Leukemia
Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and adolescents. Despite improvements in treatment outcomes over recent decades, relapsed ALL continues to be a leading cause of death by cancer in children. We propose to address this major gap in prognosis and treatment by dissecting the mechanisms of treatment resistance in ALL, aiming to identify new vulnerabilities in leukemia cells that would enable better treatments for this disease. This proposal is relevant to military mission readiness: given the high proportion of young people and parents in the active-duty military, ALL has a disproportionate impact on the health and well-being of military service members. This project will address major knowledge gaps that serve as a barrier to progress against ALL. In contrast to adult tumors that arise due to an accumulation of genetic mutations over a lifetime, childhood cancers like ALL have relatively few genetic changes. We have found that leukemia cells rely on “epigenetic” modifications, or chemical marks that modify the expression of genes without a change in the genetic sequence itself. A major mechanism by which leukemia cells can evade treatment is by generating cell-to-cell variability and diversity of such epigenetic marks, allowing each cell flexibility in turning genes on and off. This accounts for the observed heterogeneity of leukemia cells and their ability to resist chemotherapy. We apply new approaches to comprehensively analyze the dynamic epigenome in ALL at the time of diagnosis and relapse in order to dissect the mechanisms and gene targets responsible for treatment resistance in ALL. This work holds promise of clinical benefit in both the treatment and risk stratification of ALL. Currently, risk stratification of ALL based on clinical and molecular features is a critical part of treatment, allowing a reduction of toxicity in patients with low-risk disease and intensification in those with high-risk features. Given the role of epigenetic variability in driving treatment resistance of ALL, testing ALL for epigenetic instability can provide an entirely new biomarker for relapse risk that would be tremendously useful clinically. Additionally, identifying the genes that are most critical to leukemia cell resistance will inform the design of precise therapies aimed at these targets in order to improve treatment outcome. In particular, we propose to validate newly identified epigenetically altered, over-expressed oncogenes, some of which can already be targeted by existing drugs. This approach can lead to rapid translation into clinical trials. I am an M.D./Ph.D.-trained physician-scientist in pediatric oncology, pursuing an academic research career aimed at understanding and targeting epigenetic alterations in childhood cancers in order to improve outcomes. I already have a track record of academic productivity in cancer research. I will benefit from an exceptional mentor for the proposed research, who is uniquely suited to ensure successful execution of the proposed research and to guide my growth as an independent researcher in the field. Dr. Andrew Feinberg is the Bloomberg Distinguished Professor of Oncology at Johns Hopkins and Director for the Center for Epigenetics. He is world-renowned for his pioneering work in cancer epigenetics, having made the very first discoveries of altered DNA methylation in cancer and subsequently developed many of the methodologies used for its study. He has an excellent mentorship track record, with multiple prior trainees attaining senior academic positions at the forefront of their fields. The Career Development Award will be critically important to my transition from mentored researcher toward independence. This will provide a platform to build my skills and knowledge base in epigenetics and hematologic malignancies and to generate and publish original research that will lay the foundation for my future career at the forefront of cance
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110192
Entities
People
- Michael Koldobskiy
Organizations
- Johns Hopkins University
- United States Army