A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphomalike lymphoma formation in mice

摘要

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 lymphomalike 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.