T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Despite improved patient outcomes with dose intensification chemotherapy, 20% of pediatric and 50% of adult patients do relapse and ultimately die because of refractory disease. Therefore, there is a critical need for novel, highly effective anti-leukemia therapeutics. This project aims to establish the mechanisms of action of FBXL4 (F-box and leucine-rich repeat protein 4), a gene frequently inactivated in T-ALL harboring deletions in the long arm of chromosome 6 (6q-). Although 6q deletions are often large and heterogeneous, we have identified a focal 6q deletion encompassing just the FBXL4 gene. Interestingly, FBXL4 is differentially expressed during thymocyte differentiation, suggesting a functional role for FBXL4 in early T-cell development. The FBXL4 gene encodes an F-box and leucine-rich repeat factor with a predicted role in targeting specific proteins for proteasomal degradation. F-box proteins participate in essential cellular processes, including cell cycle progression, response to DNA damage, and survival. Moreover, dysregulation of F-box proteins such as FBXW7 and FBXO11 contributes to cellular transformation. At this point, the substrates and the molecular and cellular functions of the F-box protein FBXL4 remain largely unknown. To elucidate the roles and mechanisms of FBXL4 in T-ALL, I will: (1) investigate the functional consequences of FBXL4 loss in T-ALL in cell proliferation, survival, differentiation, and response to chemotherapy;(2) identify the substrates targeted for proteasomal degradation by FBXL4 in T-ALL cells;and (3) characterize the role of FBXL4 in T-cell development and transformation in vivo using conditional Fbxl4 knockout mice. Overall, these studies will characterize the roles and mechanisms of FBXL4 in the pathogenesis of T-ALL.

Public Health Relevance

The FBXL4 gene encodes a substrate recognition factor involved in the targeting of specific proteins for proteasomal degradation. FBXL4 is frequently deleted in T-cell acute lymphoblastic leukemias with 6q deletions. Here I will analyze the tumor suppressor role and mechanisms of FBXL4 in the pathogenesis of this disease using a combination of cellular, biochemical, and genetic assays in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA174099-01
Application #
8456747
Study Section
Special Emphasis Panel (ZRG1-F09-P (08))
Program Officer
Damico, Mark W
Project Start
2013-01-15
Project End
2017-01-14
Budget Start
2013-01-15
Budget End
2014-01-14
Support Year
1
Fiscal Year
2013
Total Cost
$41,377
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Haydu, J Erika; Ferrando, Adolfo A (2013) Early T-cell precursor acute lymphoblastic leukaemia. Curr Opin Hematol 20:369-73
Hartwell, Kimberly A; Miller, Peter G; Mukherjee, Siddhartha et al. (2013) Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol 9:840-8