Loss of EBF1 Expression: A Novel Murine Model for Human B-ALL

National Jewish Health, Denver CO

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Abstract

DESCRIPTION (provided by applicant): Acute lymphoblastic B cell leukemia (B-ALL) frequently strikes young children between the ages of 2 and 5, as well as older adults. Currently, most cases of pediatric ALL are readily treatable with an overall survival rate of greater than 80%. However, a significant percentage of children who initially fall into intermediate or high ris groups experience relapse and have poor survival rates. Mutations in the gene encoding the Early B cell factor 1 (Ebf1) transcription factor have been found in 25% of relapsed pediatric B-ALL cases. Beginning in common lymphoid progenitors (CLPs), EBF1 drives B lineage specification and initiates the transcription of various B cell-specific genes. EBF1 is essential fr B cell lineage commitment and subsequent differentiation. Furthermore, B cell development is impeded when Ebf1 gene dosage is reduced. Little is known regarding the potential roles of EBF1 in leukemogenesis. The studies proposed herein will define and characterize a spontaneous murine model for human B-ALL using Ebf1+/- Bcl-xLTg mice. This study will elucidate mechanisms of leukemogenesis and provide an important model for testing new therapies for children affected by high-risk B-ALL. PUBLIC HEALTH RELEVANCE: The proposed research will lead to the development of a unique mouse model of human leukemia and increase our understanding of the molecular events necessary for leukemogenesis, potentially leading to the development of new treatments for patients with high-risk and relapsed leukemia.