T cell acute lymphoblastic leukemia (T-ALL) is a cancer of T cell precursors that occurs in patients of all ages, and is especially common in older children and adolescents. Despite improvements in outcomes that have been achieved through the intensification of therapy, T-ALL remains fatal in 25% of children and 50-70% of adults. Although the molecular pathogenesis of T-ALL remains incompletely understood, aberrant activation of the MYC oncogene is a central abnormality in most cases of T-ALL, The central hypothesis of our work is that the most significant improvements in survival for these patients will come as a result of improvements in our understanding of the molecular mechanisms that mediate T-ALL leukemogenesis and MYC-induced oncogenesis. We have developed a conditional zebrafish model of MYC-induced T-ALL that closely resembles the most common subtype of human T-ALL. This zebrafish model now allows us to take full advantage of the strengths of the zebrafish system as a model of human disease through the performance of forward chemical genetic screens and conventional genetic analyses. The performance of forward chemical genetic rather than conventional mutagenesis screens will allow us to identify gene products that are targetable by small molecules, thus having obvious therapeutic implications in addition to elucidating the basic biologic processes involved. Thus, in an effort to reveal the mechanisms that mediate MYC-induced oncogenesis and T cell leukemogenesis, the specific aims of this proposal are: 1) To perform a forward chemical genetic screen in the zebrafish to identify targetable genes and pathways that are required for the survival of MYC-overexpressing thymocytes, but that are dispensable for the essential physiologic functions of MYC. 2) To establish the functional importance of genes involved in novel T-ALL genomic abnormalities as potential T-cell leukemia oncogenes and tumor suppressors using zebrafish genetic models of these lesions. The mentor and the group of advisors that Dr. Gutierrez has assembled to guide his career development represent some of the world's leading experts in cancer biology, zebrafish genetics, and chemical screens, and this environment will undoubtedly provide him with every opportunity to develop into a successful independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08CA133103-05
Application #
8292154
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$140,940
Indirect Cost
$10,440
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Gutierrez, Alejandro; Feng, Hui; Stevenson, Kristen et al. (2014) Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish. Br J Haematol 166:84-90
Gutierrez, Alejandro; Pan, Li; Groen, Richard W J et al. (2014) Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 124:644-55
Mansour, Marc R; Sanda, Takaomi; Lawton, Lee N et al. (2013) The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med 210:1545-57
Gutierrez, Alejandro; Kentsis, Alex; Sanda, Takaomi et al. (2011) The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 118:4169-73
Gutierrez, Alejandro; Snyder, Eric L; Marino-Enriquez, Adrian et al. (2011) Aberrant AKT activation drives well-differentiated liposarcoma. Proc Natl Acad Sci U S A 108:16386-91
Rudner, L A; Brown, K H; Dobrinski, K P et al. (2011) Shared acquired genomic changes in zebrafish and human T-ALL. Oncogene 30:4289-96
Gutierrez, Alejandro; Grebliunaite, Ruta; Feng, Hui et al. (2011) Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med 208:1595-603
Gutierrez, Alejandro; Dahlberg, Suzanne E; Neuberg, Donna S et al. (2010) Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol 28:3816-23
Sanda, Takaomi; Li, Xiaoyu; Gutierrez, Alejandro et al. (2010) Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia. Blood 115:1735-45
Feng, Hui; Stachura, David L; White, Richard M et al. (2010) T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell 18:353-66

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