CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis
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
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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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 1

CDK4 deficiency accelerates MYC-induced lymphomagenesis.

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CDK4 deficiency accelerates MYC-induced lymphomagenesis. (A) Kaplan-Meie...
(A) Kaplan-Meier tumor-free mice (top) and survival (bottom) for Cdk4+/+, Cdk4–/–, Eμ-MycCdk4+/+, and Eμ-MycCdk4–/– littermates. Time to appearance of palpable cervical and peripheral LNs (>5 mm in at least one dimension) is shown for Eμ-MycCdk4+/+ and Eμ-MycCdk4–/– littermates. n = number of mice in each cohort. Statistical evaluation of tumor onset is based on the Mantel-Cox test for comparison of the Kaplan-Meier event-time format and on an unpaired Student’s t test for comparison of means and SDs. P = 0.0002 for E-MycCdk4–/– versus Eμ-MycCdk4+/+ mice. (B) Eμ-MycCdk4–/– mice developed rapid-onset lymphoma. Upper right panel: the majority of 7-week-old Eμ-Myc Cdk4–/– mice were moribund and had enlarged LNs (arrows, lower right panel). At this juncture, the LNs of Eμ-MycCdk4+/+ littermates were normal. (C) Approximately 90% of cells from the enlarged LNs of 7-week-old E-MycCdk4–/– mice were B220+ cells, whereas LNs from Cdk4+/+, Cdk4–/–, and Eμ-MycCdk4+/+ mice only had 34%–40% total B220+ B cells. Results are representative of 8 different mice in each cohort; mean ± SD, P = 0.0037. FACS analyses are shown in Supplemental Figure 1A. *P < 0.05. (D) H&E staining of LNs from 7-week-old Cdk4+/+ (upper left), Cdk4–/– (lower left), Eμ-MycCdk4+/+ (upper right), and Eμ-MycCdk4–/– (lower right) littermates. Enlarged LNs of Eμ-MycCdk4–/– mice had lymphomas with disseminated characteristics (black arrows) versus normal LN architecture in Cdk4+/+, Cdk4–/–, and Eμ-MycCdk4+/+ littermates. Original magnification, ×40. (E) FACS scatter plots showing that cells of LNs from 7-week-old Eμ-MycCdk4–/– mice were composed of a homogeneous population of large (B220+) cells.