Beta-catenin Stabilization Stalls the Transition from Double-positive to Single-positive Stage and Predisposes Thymocytes to Malignant Transformation

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2007 Feb 24

PMID 17317856

Citations 67

Authors

Zhuyan Guo

Marei Dose

Damian Kovalovsky

Rui Chang

Jennifer ONeil

A Thomas Look

Harald von Boehmer

Khashayarsha Khazaie

Fotini Gounari

Affiliations

Soon will be listed here.

Abstract

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 DP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenin-induced lymphomas. Thus, beta-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

Citing Articles

CTNNB1 syndrome mouse models.

Lainscek D, Forstneric V, Mirosevic S Mamm Genome. 2025; .

PMID: 39833474 DOI: 10.1007/s00335-025-10105-3.

Stabilization of β-Catenin Directs HEB to Limit Thymic Selection.

Tousinas G, Olumide Emmanuel A, Tracy M, Arnovitz S, Friedman D, Papamarcaki T J Immunol. 2024; 213(5):641-650.

PMID: 38958395 PMC: 11333165. DOI: 10.4049/jimmunol.2400160.

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress.

Melnick A, Mullin C, Lin K, McCarter A, Liang S, Liu Y Blood. 2023; 142(25):2159-2174.

PMID: 37616559 PMC: 10733839. DOI: 10.1182/blood.2023020144.

Axin2/Conductin Is Required for Normal Haematopoiesis and T Lymphopoiesis.

de Roo J, Chhatta A, Garcia-Perez L, Naber B, Vloemans S, Salvatori D Cells. 2022; 11(17).

PMID: 36078085 PMC: 9454631. DOI: 10.3390/cells11172679.

Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation.

Arnovitz S, Mathur P, Tracy M, Mohsin A, Mondal S, Quandt J Proc Natl Acad Sci U S A. 2022; 119(32):e2201493119.

PMID: 35921443 PMC: 9371646. DOI: 10.1073/pnas.2201493119.

References

Fehling H, Krotkova A, von Boehmer H . Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature. 1995; 375(6534):795-8. DOI: 10.1038/375795a0. View

Reschly E, Spaulding C, Vilimas T, Graham W, Brumbaugh R, Aifantis I . Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms. Blood. 2006; 107(10):4115-21. PMC: 1895288. DOI: 10.1182/blood-2005-09-3551. View

Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997; 16(13):3797-804. PMC: 1170003. DOI: 10.1093/emboj/16.13.3797. View

Lu D, Zhao Y, Tawatao R, Cottam H, Sen M, Leoni L . Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004; 101(9):3118-23. PMC: 365753. DOI: 10.1073/pnas.0308648100. View

Spanopoulou E, Early A, Elliott J, Crispe N, Ladyman H, Ritter M . Complex lymphoid and epithelial thymic tumours in Thy1-myc transgenic mice. Nature. 1989; 342(6246):185-9. DOI: 10.1038/342185a0. View

Staal F, Meeldijk J, Moerer P, Jay P, van de Weerdt B, Vainio S . Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur J Immunol. 2001; 31(1):285-93. DOI: 10.1002/1521-4141(200101)31:1<285::AID-IMMU285>3.0.CO;2-D. View

Ferrando A, Neuberg D, Staunton J, Loh M, Huard C, Raimondi S . Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002; 1(1):75-87. DOI: 10.1016/s1535-6108(02)00018-1. View

Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A . Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998; 17(5):1371-84. PMC: 1170485. DOI: 10.1093/emboj/17.5.1371. View

Zweidler-McKay P, Pear W . Notch and T cell malignancy. Semin Cancer Biol. 2004; 14(5):329-40. DOI: 10.1016/j.semcancer.2004.04.012. View

10.

Noordermeer J, Klingensmith J, Perrimon N, Nusse R . dishevelled and armadillo act in the wingless signalling pathway in Drosophila. Nature. 1994; 367(6458):80-3. DOI: 10.1038/367080a0. View

11.

Weng A, Millholland J, Yashiro-Ohtani Y, Arcangeli M, Lau A, Wai C . c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006; 20(15):2096-109. PMC: 1536060. DOI: 10.1101/gad.1450406. View

12.

Staal F, Clevers H . Wnt signaling in the thymus. Curr Opin Immunol. 2003; 15(2):204-8. DOI: 10.1016/s0952-7915(03)00003-7. View

13.

Lepourcelet M, Chen Y, France D, Wang H, Crews P, Petersen F . Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004; 5(1):91-102. DOI: 10.1016/s1535-6108(03)00334-9. View

14.

Izon D, Punt J, Xu L, Karnell F, Allman D, Myung P . Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity. 2001; 14(3):253-64. DOI: 10.1016/s1074-7613(01)00107-8. View

15.

Itoh K, Antipova A, Ratcliffe M, Sokol S . Interaction of dishevelled and Xenopus axin-related protein is required for wnt signal transduction. Mol Cell Biol. 2000; 20(6):2228-38. PMC: 110839. DOI: 10.1128/MCB.20.6.2228-2238.2000. View

16.

Pear W, Aster J, Scott M, Hasserjian R, Soffer B, Sklar J . Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996; 183(5):2283-91. PMC: 2192581. DOI: 10.1084/jem.183.5.2283. View

17.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

18.

Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S . Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem. 1998; 273(18):10823-6. DOI: 10.1074/jbc.273.18.10823. View

19.

Nacht M, Jacks T . V(D)J recombination is not required for the development of lymphoma in p53-deficient mice. Cell Growth Differ. 1998; 9(2):131-8. View

20.

Palomero T, Lim W, Odom D, Sulis M, Real P, Margolin A . NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A. 2006; 103(48):18261-6. PMC: 1838740. DOI: 10.1073/pnas.0606108103. View