Abstract

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 risk 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 for 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?xL Tg 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01OD010554-02
Application #
8499561
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Contreras, Miguel A
Project Start
2012-07-01
Project End
2017-03-31
Budget Start
2012-07-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$70,200
Indirect Cost
$5,200

  Institution

Name
University of Washington
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Iwata, Terri N; Ramírez-Komo, Julita A; Park, Heon et al. (2017) Control of B lymphocyte development and functions by the mTOR signaling pathways. Cytokine Growth Factor Rev 35:47-62
Ramírez-Komo, J A; Delaney, M A; Straign, D et al. (2017) Spontaneous loss of B lineage transcription factors leads to pre-B leukemia in Ebf1+/-Bcl-xLTg mice. Oncogenesis 6:e355
Iwata, Terri N; Ramírez, Julita A; Tsang, Mark et al. (2016) Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism. J Immunol 197:2250-60
Wang, Meiqin; Ramirez, Julita; Han, Junyan et al. (2013) The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis. J Allergy Clin Immunol 132:1174-1183.e8
Chan, Maia M; Wooden, Jason M; Tsang, Mark et al. (2013) Hematopoietic protein-1 regulates the actin membrane skeleton and membrane stability in murine erythrocytes. PLoS One 8:e54902