T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for 15% of pediatric and 25% of adult ALL cases. Although the overall survival rates for children with T-ALL have improved, 25% relapse and most succumb to disease. Currently, T-ALL is treated with multi-agent chemotherapy and no targeted therapies exist. T-ALL is largely caused by activation of the TAL1 and NOTCH1 oncogenic pathways. We have shown that Tal1 contributes to leukemia by interfering with E proteins, critical regulators of lymphoid development. We also identified mutations in Notch1 as an important cooperating event and showed that mouse T-ALL growth remains dependent on Notch1. Therefore, both TAL1 and NOTCH1 contribute to T-ALL growth and survival, but it remains unknown whether human T-ALL growth can be limited in vivo by inhibiting only NOTCH1 or whether the TAL1/E2A oncogenic pathway will also need to be targeted. The overall goals of this research program are to understand how the TAL1/E2A and NOTCH1 pathways give rise to T-ALL and to use this mechanistic knowledge to test new therapeutic approaches in our mouse and newly established human T-ALL models. We hypothesize that the high rates of therapeutic relapse observed in T-ALL patients reflects an inability to eliminate leukemia-initiating cells (L-ICs), a rare population of leukemic cells required to initiate and perpetuate disease. Using our mouse T-ALL models, we demonstrate that committed thymic progenitors are enriched in disease potential and that Notch1 inhibition reduces mouse L-IC activity. A goal of this proposal is to purify and characterize the mouse L-IC and to determine how Notch1 mediates L-IC self-renewal and whether Tal1 also contributes (Aim1). Our preliminary studies show that silencing the TAL1 oncogene sensitizes human T-ALL cells to the effects of NOTCH1 inhibition and induces apoptosis. A final objective of this proposal is to develop novel TAL1 inhibitors and to test whether TAL1 and NOTCH1 inhibition is sufficient to eliminate human L-ICs and prolong the survival of immunodeficient NOD-scid IL2R3null mice engrafted with primary pediatric T-ALL cells.

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The overall goal of this research program is to understand how the TAL1 and NOTCH1 oncogenes cooperate to cause T cell leukemia. The work proposed will use mouse and human models of the disease to determine whether targeting TAL1 and/or NOTCH1 reduces leukemia initiating cell (L-IC) growth and results in long term survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-OBT-S (02))
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Mufson, R Allan
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University of Massachusetts Medical School Worcester
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Carr, Michael I; Roderick, Justine E; Gannon, Hugh S et al. (2016) Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis. Cell Rep 16:2618-29
Roderick, Justine E; Tesell, Jessica; Shultz, Leonard D et al. (2014) c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood 123:1040-50
Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70
Reynolds, C; Roderick, J E; LaBelle, J L et al. (2014) Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia 28:1819-27
Gutierrez, Alejandro; Roderick, Justine E; Kelliher, Michelle A (2014) Leukemia propagating cells Akt up. Cancer Cell 25:263-5
Sanda, Takaomi; Tyner, Jeffrey W; Gutierrez, Alejandro et al. (2013) TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov 3:564-77
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
Simmons, Matthew J; Serra, Ryan; Hermance, Nicole et al. (2012) NOTCH1 inhibition in vivo results in mammary tumor regression and reduced mammary tumorsphere-forming activity in vitro. Breast Cancer Res 14:R126
Sawai, Catherine M; Freund, Jacquelyn; Oh, Philmo et al. (2012) Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell 22:452-65
Sanda, Takaomi; Lawton, Lee N; Barrasa, M Inmaculada et al. (2012) Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia. Cancer Cell 22:209-21

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