This proposal is based on the central hypothesis that improved understanding of the molecular pathways that contributing to the disordered regulation of cell proliferation, differentiation, and apoptosis in T-cell lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) will ultimately lead to improved therapy of these diseases. The research will be accomplished through the coordinated efforts of 5 research projects and 2 cores. In Project 1, Tom Look will work closely with Rick Young to identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. In Project 2, Harald von Boehmer will identify molecular pathways that cooperate with Notch1 signaling in lymphomagenesis by analyzing the impact of insertional mutagenesis, epigenetic regulation, and miRNA-dependent regulation on the generation of T-ALL from in Notch1 overexpressing T-cell progenitors. In Project 3, Peter Sicinski will study the molecular function of D-cyclins in Notch-driven murine T-ALL model (together with Harald von Boehmer) and in human T-ALL (with Tom Look). In Project 4, Fred Alt will elucidate molecular mechanisms and activated pathways associated with recurrent chromosomal translocations in thymic leukemias and lymphomas. In Project 5, Rick Young will identify the epigenetic mechanisms regulating normal T cell development and leukemogenesis and link them to the oncogenic action of TAL1 and Notch1 in T-ALL. Discoveries in murine models made by Drs. von Boehmer, Sicinski, Alt and Young will be immediately translated to determine relevance to human T-ALL/LBL molecular pathogenesis in collaboration with Dr. Look. These projects will be augmented with a Biostatistics Core (Donna Neuberg), to assist with the analysis of microarray data and the optimal design of animal experiments;and an Administrative Core (Tom Look and Harald von Boehmer), to oversee the administration and coordination of the research interactions among program investigators. Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole.

Public Health Relevance

Successful completion of this 5-year renewal of our program will improve understanding of how T-cell regulatory pathways are disrupted to initiate and maintain the transformed phenotype in T-ALL and T-LBL, with the long-term goal to pinpoint genes whose inhibition could lead to the development of new and highly specific treatment strategies for these malignant diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M et al. (2016) Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol 12:876-84
Hnisz, Denes; Weintraub, Abraham S; Day, Daniel S et al. (2016) Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351:1454-8
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
Tan, S H; Yam, A W Y; Lawton, L N et al. (2016) TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia 30:959-62
Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86
Jiang, Wenxia; Lee, Brian J; Li, Chen et al. (2015) Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency. Blood 125:2665-8
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
Oldridge, Derek A; Wood, Andrew C; Weichert-Leahey, Nina et al. (2015) Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528:418-21
Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20
Chipumuro, Edmond; Marco, Eugenio; Christensen, Camilla L et al. (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126-39

Showing the most recent 10 out of 58 publications