Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma

Monti, Stefano; Chapuy, Bjoern; Takeyama, Kunihiko; Rodig, Scott J.; Hao, Yansheng; Yeda, Kelly T.; Inguilizian, Haig; Mermel, Craig H.; Currie, Treeve; Doğan, Ahmet; Kutok, Jeffery L.; Beroukhim, Rameen; Neuberg, Donna; Habermann, Thomas M.; Getz, Gad; Kung, Andrew L.; Golub, Todd R.; Shipp, Margaret A.

doi:10.1016/j.ccr.2012.07.014

Cited by 188 publications

(259 citation statements)

References 66 publications

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“…Indeed, genomic instability typifies Eμ-Myc Cdk4 -/-B cell lymphoma, which selectively accumulates complex genomic abnormalities and is associated with the induction of several oncogenes that have been implicated in B cell malignancies. Collectively, increased which include copy gains of all possible genes, and that of these, there was a low frequency (only 13%) that had amplified CDK4 (52). Further, IHC analyses have shown that indolent FLs express no (12 of 21, 57%) or very low (9 of 12, 43%) levels of CDK4 and that 68% (15 of 22) of DLBCLs have no or low CDK4 levels (6 of 22 were negative and 9 of 22 had low levels of CDK4 (53).…”

Section: Discussionmentioning

confidence: 99%

CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

Lu¹,

Yong-sheng²,

Xu³

et al. 2014

J. Clin. Invest.

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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. IntroductionMYC oncoproteins function as transcription factors that coordinate the expression of a large cast of genes that direct cell metabolism, growth, and division. Elevated MYC levels are a hallmark of rapidly dividing human malignancies, and this has major effects on cell physiology, provoking hyperproliferative and DNA damage responses (DDRs) as well as apoptosis (1, 2). In the Eμ-Myc transgenic mouse, a model of human B cell lymphoma (3), bypass of these three checkpoints accompanies malignant transformation. First, MYC activates a DDR in premalignant B cells (4), perhaps via MYC's effects on unscheduled firing of DNA replication origins (5). Second, MYC induces the Arf tumor suppressor that inactivates the E3 ubiquitin ligase MDM2, leading to p53 stabilization and p53-dependent apoptosis (6, 7). Third, MYC triggers p27 Kip1 destruction by the SCF Skp2 complex by inducing Cks1 expression as well as the expression of cyclin D2 (Ccnd2), which sequesters p27 Kip1 , and both responses likely contribute to the hyperproliferative response of MYC (8).c-MYC directly induces the transcription of Cdk4 (9), a G1 serine/ threonine kinase (10, 11) that is required for tumorigenesis in some contexts (12)(13)(14). CDK4 activation requires binding to the regulatory cyclin subunits cyclin D1, -D2, or -D3. CDK4:cyclin D complexes phosphorylate and inactivate the retinoblastoma (Rb) tumorsuppressor protein, releasing E2F transcription factors that regulate genes necessary for entry and progression through the S phase (15).

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Section: Discussionmentioning

confidence: 99%

CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

Lu¹,

Yong-sheng²,

Xu³

et al. 2014

J. Clin. Invest.

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“…14 Although only 15% to 20% of DLBCLs have inactivating TP53 mutations, the majority of these tumors exhibit complementary CNAs that decrease p53 activity and perturb cell-cycle regulation.…”

Section: Introductionmentioning

confidence: 99%

Targetable genetic features of primary testicular and primary central nervous system lymphomas

Chapuy

Roemer

Stewart

et al. 2016

Blood

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450

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“…The cadherin molecules are important in maintaining the adherent junctions via calcium mediated cell-cell interaction [17]. One of the most predominant cadherin molecules is E-Cadherin, a transmembrane protein that creates ECAD interaction between 2 cells (calcium dependent) [1,11]. It is logical to summarize that CK7 can mark for PCa of glandular origin, thus important in characterizing neoplasm tissue mass at the interphase of epithelium and glandular tissue (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Only cells that over express p53 or p21 may be assessed using Ki-67. Thus, the level of Ki-67 expression may be used to determine the cell proliferation status [11]. Typically, actively growing prostate cancer cells are few and the rapidity of growth is at a reduced rate.…”

Section: Introductionmentioning

confidence: 99%

Cell Proliferation and Epithelia Profile in Prostate Cancer and Benign Prostatic Hyperplasia

O.M.¹,

P.T.²,

D.T.³

et al. 2014

TOCJ

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Abstract:Objectives: Prostate cancer (PCa) and Benign Prostatic Hyperplasia (BPH) are the leading cause of urinary tract disorders in males both of which are characterized by rapid proliferation of cells. This study characterizes both Ki-67 and E-Cadherin profiles in BPH and PCa biopsies to determine and compare the extent of aggressiveness of cell proliferation in BPH and PCa.Method: Biopsies were collected from patients clinically diagnosed to be suffering from PCa or BPH and were immunohistochemically labelled using Anti-Ki-67 and Anti-ECAD monoclonal antibodies. The sections were treated with urea followed by incubation in a microwave to activate the antigens. Primary antibody treatment was done in biotinylated goat serum, blocking was done with bovine serum albumin (BSA) and finally secondary antibody staining using Anti-Ki-67 and Anti-ECAD monoclonal antibodies. Results:The expression level of Ki-67 corresponded to the rate of proliferation and size of the tumor cell mass in both PCa and BPH. ECAD expression was highly positive in BPH and less positive in PCa-showing onset of malignancy in PCa. Certain cell clumps (metastases) stained highly positive to Ki-67 and were located at random intervals within the tissue of PCa biopsies, this type of distribution also coincided with ECAD immunonegativity. Conclusion:Ki-67 expression indicates the rate of cell proliferation and the aggressiveness of such tumors, while ECAD shows defective cytoskeleton and extent of malignancy. Correlating ECAD and Ki-67 gives a direct relationship between the rate of cell division, tumor invasion and epithelia structure. This also covers both glandular and fibromuscular epithelium

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Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma

Cited by 188 publications

References 66 publications

CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

Targetable genetic features of primary testicular and primary central nervous system lymphomas

Cell Proliferation and Epithelia Profile in Prostate Cancer and Benign Prostatic Hyperplasia

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