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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096899-08
Application #
8472445
Study Section
Special Emphasis Panel (ZRG1-OBT-S (02))
Program Officer
Mufson, R Allan
Project Start
2002-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$300,567
Indirect Cost
$117,852
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
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
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
Gutierrez, Alejandro; Roderick, Justine E; Kelliher, Michelle A (2014) Leukemia propagating cells Akt up. Cancer Cell 25:263-5
Draheim, K M; Hermance, N; Yang, Y et al. (2011) A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice. Oncogene 30:1252-60
Tatarek, Jessica; Cullion, Kathleen; Ashworth, Todd et al. (2011) Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood 118:1579-90
Cullion, Kathleen; Draheim, Kyle M; Hermance, Nicole et al. (2009) Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 113:6172-81
Sharma, Vishva Mitra; Draheim, Kyle M; Kelliher, Michelle A (2007) The Notch1/c-Myc pathway in T cell leukemia. Cell Cycle 6:927-30
Shank-Calvo, J A; Draheim, K; Bhasin, M et al. (2006) p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice. Oncogene 25:3023-31