期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 180, 期 4, 页码 1688-1701出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.01.004
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类别
资金
- Ligue Contre le Cancer (comite departemental de la Haute-Vienne, Creuse, Correze, Gironde et Landes)
- Comite d'Organisation sur la Recherche sur le Cancer en Limousin
- Conseil Regional du Limousin
- ANR
- Lions Club de la Correze
- Association pour la Recherche sur le Cancer (ARC)
- Region Aquitaine
- MICROENVIMET [FP7-HEALTHF2-2008-201279]
- INCa
Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24c) mice with Myc-3'RR transgenic mice. The Cdk4(R24c) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24c) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24c) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24c) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL. (Am J Pathol 2012, 180: 1688-1701; DOL. 10.1016/j.ajpath.2012.01.004)
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