CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis
Yuanzhi Lu, … , John L. Cleveland, Xianghong Zou
Yuanzhi Lu, … , John L. Cleveland, Xianghong Zou
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1672-1684. https://doi.org/10.1172/JCI63139.
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Research Article Oncology

CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

Abstract

The G1 kinase CDK4 is amplified or overexpressed in some human tumors and promotes tumorigenesis by inhibiting known tumor suppressors. Here, we report that CDK4 deficiency markedly accelerated lymphoma development in the Eμ-Myc transgenic mouse model of B lymphoma and that silencing or loss of CDK4 augmented the tumorigenic potential of Myc-driven mouse and human B cell lymphoma in transplant models. Accelerated disease in CDK4-deficient Eμ-Myc transgenic mice was associated with rampant genomic instability that was provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. Specifically, CDK4 phosphorylated and inactivated FOXO1, which prevented FOXO1-dependent induction of Rag1 and Rag2 transcription. CDK4-deficient Eμ-Myc B cells had high levels of the active form of FOXO1 and elevated RAG1 and RAG2. Furthermore, overexpression of RAG1 and RAG2 accelerated lymphoma development in a transplant model, with RAG1/2-expressing tumors exhibiting hallmarks of genomic instability. Evaluation of human tumor samples revealed that CDK4 expression was markedly suppressed, while FOXO1 expression was elevated, in several subtypes of human non-Hodgkin B cell lymphoma. Collectively, these findings establish a context-specific tumor suppressor function for CDK4 that prevents genomic instability, which contributes to B cell lymphoma. Furthermore, our data suggest that targeting CDK4 may increase the risk for the development and/or progression of lymphoma.

Authors

Yuanzhi Lu, Yongsheng Wu, Xiaoling Feng, Rulong Shen, Jing H. Wang, Mohammad Fallahi, Weimin Li, Chunying Yang, William Hankey, Weiqiang Zhao, Ramesh K. Ganju, Ming O. Li, John L. Cleveland, Xianghong Zou

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Figure 3

CDK4 deficiency augments genomic instability of Myc-driven lymphoma.

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CDK4 deficiency augments genomic instability of Myc-driven lymphoma. (...
(A) Karyotype of E-MycCdk4+/+ lymphoma. Trisomy of chr 6 and/or chr 5 was evident in most lymphomas. (B) Abnormal karyotypes are a hallmark of Eμ-MycCdk4–/– lymphomas, including deletions of chr 6 at region C2, translocation of chr 6 and chr 12 with breakpoints (6;12)(C2;F1), trisomy of chr 18, loss of chr X, deletions of chr 3 and chr 16 at regions F2.2 and 16, respectively, translocation between chr 3 and chr 16, and the der(16) with [+der(3)t(3;16)(F2.2;C2),der(16)t(3;16) (F2.2;C2)ins(16;?)(C2;?)]. Karyotypes shown are representative of 20 cells for each lymphoma. (C) Statistical analysis of genomic instability in Eμ-MycCdk4–/– versus Eμ-MycCdk4+/+ lymphomas. The numbers of aberrant chromosomes (translocation, partial genomic loss and gain) per lymphoma are shown for Eμ-MycCdk4–/– and Eμ-MycCdk4+/+ lymphomas. Eμ-MycCdk4+/+ lymphomas (n = 6) with 0, 1, 2, and greater than or equal to 3 aberrant chromosomes are indicated. All Eμ-MycCdk4–/– lymphomas (n = 6) had more than 3 aberrant chromosomes (Supplemental Table 3). (D) FISH analyses of Eμ-MycCdk4–/– lymphomas. Metaphase samples of B220+ cells from Eμ-MycCdk4+/+ and Eμ-MycCdk4–/– lymphomas were assessed by FISH with 5′ (green) and 3′ (red) Igh probes that flank the 2Mb Igh locus on chr 12 (37). An intact Igh locus had colocalized red and green signals, while a broken locus had split red and green signals. FISH analyses confirmed complex translocations in Eμ-MycCdk4–/– lymphomas. Original magnification, ×1,500. Ch, constant (C) region of Igh locus; Vh, variable (V) region of Igh locus. (E) Statistical analysis of translocated versus wild-type Igh loci in Eμ-MycCdk4–/– and Eμ-MycCdk4+/+ lymphomas (n = 6, P < 0.01).