期刊
BLOOD
卷 109, 期 12, 页码 5463-5472出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-11-059071
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- NCI NIH HHS [R01 CA104547, R01 CA104547-01A1] Funding Source: Medline
- NIAID NIH HHS [R01 AI059676-01, R01 AI059676] Funding Source: Medline
- NIDDK NIH HHS [P30 DK34928, P30 DK034928] Funding Source: Medline
Activation of beta-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated beta-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. beta-Catenin-induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DIP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenininduced lymphomas. Thus, beta-catenin activation may provide a mechanism forthe induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.
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