T cell acute lymphoblastic leukemia (T-ALL) is a very malignant disease with few effective treatments. A majority of T-ALL cases are associated with an aberrant expression of the TAL1/SCL gene, which encodes two basic helix-loop-helix (bHLH) proteins capable of forming heterodimers with other bHLH E proteins such as E2A and HEB. Evidence accumulated by our laboratory and others have established that TAL1/SCL proteins act as inhibitors of E proteins, which are both tumor suppressors and regulators of lymphocyte development. Transgenic mice expressing TAL1/SCL develop T cell lymphoma in a similar manner as E2A deficient mice or transgenic mice carrying the Id1 gene, which encodes a dominant-negative inhibitor of E proteins. Therefore, in this renewal proposal, we focus our effort on understanding the mechanisms of T cell lymphomagenesis due to loss of E protein function. We will first ask if the developmental stage at which E protein function is inhibited is crucial for lymphomagenesis. We will also ask if other oncogenic factors such as activated Notch receptors act by interfering with E protein function. We will then test the hypothesis that hyper-responsiveness to pre-T cell receptor or T cell receptor signaling resulting from loss of E protein function combines with secondary mutations of anti-apoptotic genes to promote tumorigenesis. Finally, we will use retroviral insertional mutagenesis to search for additional factors capable of facilitating leukemogenesis in TAL1/SCL or Id1 transgenic mice. Findings from these studies will advance our knowledge regarding the roles of E proteins in T cell development and tumor suppression, with the goal of providing the basis for effective therapies against T-ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077553-07
Application #
7032275
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
1999-01-01
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
7
Fiscal Year
2006
Total Cost
$288,536
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Long, Courtney L; Berry, William L; Zhao, Ying et al. (2012) E proteins regulate osteoclast maturation and survival. J Bone Miner Res 27:2476-89
Dudley, Darryll D; Wang, Hong-Cheng; Sun, Xiao-Hong (2009) Hes1 potentiates T cell lymphomagenesis by up-regulating a subset of notch target genes. PLoS One 4:e6678
Wang, Hong-Cheng; Perry, S Scott; Sun, Xiao-Hong (2009) Id1 attenuates Notch signaling and impairs T-cell commitment by elevating Deltex1 expression. Mol Cell Biol 29:4640-52
Nie, Lei; Wu, Huaqing; Sun, Xiao-Hong (2008) Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. J Biol Chem 283:684-92
Nie, Lei; Perry, S Scott; Zhao, Ying et al. (2008) Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals. Mol Cell Biol 28:2078-90
Yang, Yuanzheng; Wang, Hong-Cheng; Sun, Xiao-Hong (2008) Id1 induces apoptosis through inhibition of RORgammat expression. BMC Immunol 9:20
Yang, Yuanzheng; Liou, Hsiou-Chi; Sun, Xiao-Hong (2006) Id1 potentiates NF-kappaB activation upon T cell receptor signaling. J Biol Chem 281:34989-96
Huang, Zhong; Nie, Lei; Xu, Min et al. (2004) Notch-induced E2A degradation requires CHIP and Hsc70 as novel facilitators of ubiquitination. Mol Cell Biol 24:8951-62
Qi, Zengbiao; Sun, Xiao-Hong (2004) Hyperresponse to T-cell receptor signaling and apoptosis of Id1 transgenic thymocytes. Mol Cell Biol 24:7313-23
Xu, Min; Nie, Lei; Kim, Seung-Hwan et al. (2003) STAT5-induced Id-1 transcription involves recruitment of HDAC1 and deacetylation of C/EBPbeta. EMBO J 22:893-904

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