A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphoma-like lymphoma formation in mice.
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.
Faculty of Medicine, UMR CNRS 6101, Limoges, France.
Christelle
C
Vincent-Fabert
Rémi
R
Fiancette
Pauline
P
Rouaud
Christel
C
Baudet
Véronique
V
Truffinet
Virginie
V
Magnone
Angélique
A
Guillaudeau
Michel
M
Cogné
Pierre
P
Dubus
Yves
Y
Denizot
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D016259:Genes, myc; D007136:Immunoglobulins / Q000096:biosynthesis; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin
C530105:Ccnd1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007136:Immunoglobulins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D019938:Cyclin D1; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4