Leukemias are a heterogeneous group of cancers with various etiology, incidence, and prognosis which are classified by their lineage (lymphoid and myeloid) and cell maturity. T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive neoplasm of the bone marrow and accounts for ?20% of all cases of adult ALL. Despite improvement in the clinical management and survival (?85-90%) of childhood leukemia, the prognosis of adult T-ALL remains poor due to a high incidence of relapse with frequent central nervous system involvement. Transformation of T-cells involves the cooperative effect of oncogenes and tumor suppressors, which deregulate the mechanisms controlling normal proliferation, differentiation, and survival. Activating mutations of NOTCH1, a class I transmembrane receptor critical for lymphopoiesis, have been implicated in over 50% of T-ALL. The high rate of NOTCH1 mutations suggest a potential vulnerability for targeted intervention; however, the nature of these mutations have proven difficult to target. In addition to genetic changes, an emerging research topic in T-ALL is the identification of chromatin modifying enzymes that cooperate with genetic mutations to cause leukemic self-renewal and drug resistance. We recently discovered that histone demethylase KDM2B regulates lymphoid commitment through modulation of NOTCH1 signaling and is required for the oncogenicity of human T-ALL cell lines. Here, we describe compound mutant mice that express constitutively active NOTCH1 in lymphoid progenitors in the context of either ablation or overexpression of KDM2B. We propose to study this histone demethylase (a) in the initiation and maintenance of NOTCH1-driven T- ALL, and (b) map the transcriptional and epigenetic networks involved in T-cell transformation. Overall, successful completion of this proposal will shed light into the interplay between NOTCH1 signaling and epigenetic alterations that drive T-cell transformation, and will uncover new targets for therapeutic intervention.

Public Health Relevance

T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive neoplasm frequently driven by activating mutations of the NOTCH1 receptor. Despite treatment advances in T-ALL, there are still important biologic and therapeutic questions that need to be answered to improve survival. We identified histone demethylase KDM2B as important regulator of NOTCH1 signaling and propose to characterize and validate its role as a new therapeutic target in T-ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA219523-01A1
Application #
9654846
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Duglas Tabor, Yvonne
Project Start
2018-12-03
Project End
2020-11-30
Budget Start
2018-12-03
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
George Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052