β-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

Zhuyan Guo, Marei Dose, Damian Kovalovsky, Rui Chang, Jennifer O'Neil, A. Thomas Look, Harald Von Boehmer, Khashayarsha Khazaie, Fotini Gounari

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Activation of β-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 β-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. β-Catenin-induced thymic lymphomas have a leukemic arrest at the early DPstage. 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 DP thymocytes with stabilized β-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in β-catenin-induced lymphomas. Thus, β-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

Original languageEnglish (US)
Pages (from-to)5463-5472
Number of pages10
JournalBlood
Volume109
Issue number12
DOIs
StatePublished - Jun 15 2007
Externally publishedYes

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Catenins
Thymocytes
Stabilization
Chemical activation
Lymphoma
T-cells
Notch Receptors
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Ablation
Colonic Neoplasms
Up-Regulation
T-Lymphocytes
Molecules

ASJC Scopus subject areas

  • Hematology

Cite this

β-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation. / Guo, Zhuyan; Dose, Marei; Kovalovsky, Damian; Chang, Rui; O'Neil, Jennifer; Look, A. Thomas; Von Boehmer, Harald; Khazaie, Khashayarsha; Gounari, Fotini.

In: Blood, Vol. 109, No. 12, 15.06.2007, p. 5463-5472.

Research output: Contribution to journalArticle

Guo, Zhuyan ; Dose, Marei ; Kovalovsky, Damian ; Chang, Rui ; O'Neil, Jennifer ; Look, A. Thomas ; Von Boehmer, Harald ; Khazaie, Khashayarsha ; Gounari, Fotini. / β-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation. In: Blood. 2007 ; Vol. 109, No. 12. pp. 5463-5472.
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N2 - Activation of β-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 β-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. β-Catenin-induced thymic lymphomas have a leukemic arrest at the early DPstage. 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 DP thymocytes with stabilized β-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in β-catenin-induced lymphomas. Thus, β-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

AB - Activation of β-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 β-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. β-Catenin-induced thymic lymphomas have a leukemic arrest at the early DPstage. 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 DP thymocytes with stabilized β-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in β-catenin-induced lymphomas. Thus, β-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

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