Toward Understanding Mechanisms for the Development of Radiation-induced Hematologic Malignancies
Exposure of the bone marrow (BM) to ionizing radiation from cancer therapy or a nuclear disaster is associated with a significant increase in the risk of developing secondary hematologic malignancies. Due to an ever-increasing number of cancer survivors and the threat of nuclear terrorism, there is an unmet need to develop effective strategies for risk assessment, prevention, and mitigation of radiation-induced hematologic malignancies. The long-term goal of my research program is to study how ionizing radiation alters the microenvironment and cell competition within the stem/progenitor pool to promote the development of secondary hematologic cancers.
Project 1: Ionizing radiation promotes the expansion of premalignant cells in the thymus
Experimentally, ionizing radiation effectively induces thymic (T-cell) lymphomas in wild-type mice. Although mouse models of radiation-induced thymic lymphomas have been used to study various aspects of radiation and cancer biology, the fundamental mechanisms for the development of radiation-induced T-lymphoma remain incompletely understood. The goal of this project is to use novel genetically engineered mice and next-generation genetic tools to investigate how radiation impacts initiation, expansion and malignant transformation of thymic progenitor into thymic lymphomas.
Proposed models of radiation-induced thymic lymphoma. We hypothesize that radiation promotes lymphoma formation by decreasing cell competition from BM-derived hematopoietic stem/progenitor cells (HSPCs) (Aim 1), which promotes clonal expansion of thymic-intrinsic progenitors with oncogenic potential (Aim 2) that undergoes genetic and epigenetic evolution for malignant transformation (Aim 3).
Project 2: Minimizing the risk of therapy-related myeloid neoplasms: targeting p53 mutant cells
The goal of this project is to reduce the risk of developing therapy-related myeloid neoplasms (t-MNs) in patients who receive chemotherapy and/or radiotherapy. About 30% of t-MNs evolve from rare founding clones that harbor mutations in the tumor suppressor p53. We are using mouse models to investigate novel strategies that can either prevent the expansion of p53 mutant cells or selectively deplete these cells before they undergo malignant transformation.
Developing novel strategies to ameliorate radiation-induced gastrointestinal toxicity
Delivery of adequate doses of radiation therapy to treat tumors in the abdomen is often limited by normal tissue toxicity of the gastrointestinal (GI) tract. The GI acute radiation syndrome (GI-ARS) occurs after high dose abdominal radiation exposure, which induces extensive damage to crypt stem cells of the small intestines. Severe damage to intestinal stem cells impairs regeneration of the intestinal epithelium, which can result in atrophy of the villi, loss of mucosal barrier, and sepsis. Currently, there are no drugs approved by the US FDA to specifically treat the GI-ARS beyond standard supportive care. Therefore, we are interested in developing novel therapeutic strategies that preserve the crypt cells and promote regeneration of the GI epithelium after radiation.