This project aims to establish the oncogenic mechanisms activated by ETV6 mutations in T- cell acute lymphoblastic leukemia (T-ALL). Our central hypothesis is that ETV6 mutations found in T- ALL result in expression of dominant negative ETV6 isoforms whose expression disrupts specific transcriptional regulatory networks that control cell proliferation, differentiation and survival in T-cell progenitor cells. In additin, we propose that ETV6 mutations cooperate with activating mutations in loss of function mutations and deletions in EZH2 in T-ALL. Thus, the goals of this research proposal are to define the transcriptional programs and oncogenic pathways responsible for the pathogenesis of mutant ETV6 induced T-ALL. To achieve these objectives we propose: (i) to define the transcriptional program controlled by mutant ETV6 in T-ALL;and (iii) to analyze the genetics of mutant ETV6 induced transformation using a mouse models of mutant ETV6 induced T-ALL.

Public Health Relevance

This project aims to analyze the mechanisms of T-cell transformation induced by mutations in the ETV6 tumor suppressor gene using a combination of genomic tools and genetic approaches. Elucidation of the specific mechanisms operating downstream of mutant ETV6 in T-ALL will provide important novel insight on the pathogenic mechanisms operating in immature T-ALLs, a poorly characterized leukemia with poor prognosis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA172398-02
Application #
8608504
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Oshima, Koichi; Khiabanian, Hossein; da Silva-Almeida, Ana C et al. (2016) Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 113:11306-11311
Haydu, J Erika; Ferrando, Adolfo A (2013) Early T-cell precursor acute lymphoblastic leukaemia. Curr Opin Hematol 20:369-73