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.
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.
| Ferrando, Adolfo (2018) Can one target T-cell ALL? Best Pract Res Clin Haematol 31:361-366 |
| Wang, K; Sanchez-Martin, M; Wang, X et al. (2017) Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias. Leukemia 31:151-158 |
| Welsch, Matthew E; Kaplan, Anna; Chambers, Jennifer M et al. (2017) Multivalent Small-Molecule Pan-RAS Inhibitors. Cell 168:878-889.e29 |
| 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 |
