T-cell acute lymphoblastic leukemia (T-ALL), which comprises 10% to 15% of ALL cases in pediatric patients, is especially common in teenagers and accounts for 25% of ALL cases in adults. Despite significant advances in long-term event-free survival, current treatments for T-ALL are often toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients. The central hypothesis for this research is that in-depth knowledge of multi-step pathways of molecular pathogenesis is needed to propel progress toward personalized medicine for T-ALL. An important long-term goal is to find genes encoding new targets and molecular pathways for the development of more specific and less toxic drugs for the treatment of T-ALL. This goal will be achieved through three specific aims.
In Aim 1, we will build on work conducted during the last funding period of this project to identify oncogenic pathways and therapeutic targets in high risk T-ALLs with the absence of biallelic TCRy chain deletions (ABD subtype) and PTEN loss. We will conduct BH3-profillng to specifically target anti-apoptotic pathways and also test mTOR inhibitors to improve therapy for the high risk ABD subgroup.
In Aim 2, we will build on our exciting new preliminary data to determine the mechanisms of TYK2 pathway dependence and analyze selective pathway inhibitors in T-ALL. We recently discovered that the majority of human T-ALLs depend on TYK2 tyrosine activity for growth an survival, and In this Aim we will interrogate this pathway in detail to develop potent inhibitors that specifically target T-ALL cells.
In Aim 3, we will pursue our discovery during the last funding period that LEF1 Is a tumor suppressor in T-ALL to define the mechanisms through which loss of LEF1 contributes to T-ALL using zebrafish and primagraft T-ALL models. Each of these Alms involves numerous opportunities to interact closely with other projects in this program, with the ultimate goal of bringing novel targeted therapies to the bedside for children and adults with T-ALL.

Public Health Relevance

The intensification of therapy for children with T-cell acute lymphoblastic leukemia (T-ALL) has improved clinical outcomes substantially, but first-line therapy continues to fail in approximately 25% of children and in more than 50% of adults, and after initial failure these patients have a very poor prognosis. In this research project, we will test inhibitors of the PI3K/AKT/mT0R axis and anti-apoptotic pathways, the TYK2 tyrosine kinase and pathways disrupted by the loss of LEF1 to develop new targeted therapies for high risk T-ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA176746-04
Application #
8901763
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Merritt, William D
Project Start
2012-09-24
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
Mansour, Marc R; He, Shuning; Li, Zhaodong et al. (2018) JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia. J Exp Med 215:1929-1945
Rahman, Sunniyat; Magnussen, Michael; León, Theresa E et al. (2017) Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia. Blood 129:3221-3226
Akahane, Koshi; Li, Zhaodong; Etchin, Julia et al. (2017) Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia. Br J Haematol 177:271-282
Akahane, K; Sanda, T; Mansour, M R et al. (2016) HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia 30:219-28
Anderson, N M; Li, D; Peng, H L et al. (2016) The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 30:1365-74
Mansour, Marc R; Reed, Casie; Eisenberg, Amy R et al. (2015) Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia. Br J Haematol 168:230-8
Anderson, N M; Harrold, I; Mansour, M R et al. (2014) BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28:1145-8
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
Mansour, Marc R; Abraham, Brian J; Anders, Lars et al. (2014) Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373-7
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

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