Heterogeneous Abnormalities of CCND1 and RB1 in Primary Cutaneous T-Cell Lymphomas Suggesting Impaired Cell Cycle Control in Disease Pathogenesis

Mao, Xin; Orchard, Guy; Vonderheid, Eric C.; Nowell̀, Peter C.; Bagot, Martine; Bensussan, Armand; Russell‐Jones, Robin; Young, Bryan D.; Whittaker, Sean

doi:10.1038/sj.jid.5700224

Cited by 35 publications

(33 citation statements)

References 38 publications

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“…We also found a highly recurrent region of loss within 9q13-q21. 33, present in 9 of 28 samples (32%), which was not previously reported among the common deletions in CTCL (Table 1; Fig. 1).…”

Section: Resultssupporting

confidence: 47%

“…Our results indicate that large regions of low-level copy number gains (inferred copy number between 2.4 and 3.4), likely corresponding to duplication events, are prevalent in this malignancy. Similarly, HDs were not frequently observed in our series of SS patients, and although all those identified matched well-known tumor suppressor genes (CDKN2A, CDKN2B, RB1) already described in CTCL (30,33,34), they do not occur in the highly recurrent regions of copy number loss. This suggests that they might represent sporadic events further worsening the pattern of chromosomal aberrations of the tumor cell.…”

Section: Discussionmentioning

confidence: 90%

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Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

et al. 2009

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In this study, we used single nucleotide polymorphism and comparative genomic hybridization array to study DNA copy number changes and loss of heterozygosity for 28 patients affected by Sézary syndrome (SS), a rare form of cutaneous Tcell lymphoma (CTCL). Our data identified, further confirming previous studies, recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71% and 68% of cases, respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in >30% of tumors: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. Individual chromosomal aberrations did not show a significant correlation with prognosis; however, when more than three recurrent chromosomal alterations (gain or loss) were considered, a statistical association was observed using Kaplan-Meier survival analysis. Integrating mapping and transcriptional data, we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer-related genes such as members of the NF-κB pathway (BAG4, BTRC, NKIRAS2, PSMD3, and TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times, we identify several common candidates that might exert critical roles in SS, such as BUB3 and PIP5K1B. Altogether, our study confirms and maps more precisely the regions of gain and loss and, combined to transcriptional profiles, suggests a novel set of genes of potential interest in SS. [Cancer Res 2009;69(21):8438-46]

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Section: Resultssupporting

confidence: 47%

Section: Discussionmentioning

confidence: 90%

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

et al. 2009

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“…Additionally, we evaluated the expression of the PTEN, RB1, and p53 tumor suppressor genes, whose expression levels are often dysregulated in T cell lymphomas (Kanavaros et al 2001, Møller et al 2002, Mao et al 2006. We only observed a decrease in the expression of p53 in the tumors from hyperthyroid animals compared with those from hypothyroid or euthyroid animals, and this result was anticipated due to its key role in hematological malignancies (Kanavaros et al 2001, Møller et al 2002.…”

Section: Figurementioning

confidence: 83%

“…Furthermore, cyclin D3 overexpression is associated with a higher proliferation rate, as well as with lower p27/KIP1 and altered p53 expression (Møller et al 2001). The positive regulation of cyclins D1 and D3 has been shown to be associated with a poor prognosis in patients with lymphoma (Zukerberg et al 1995, Kanavaros et al 2001, Mao et al 2006. Cyclin E1 is a key mediator of T-cell lymphomagenesis and regulates the transition between G1 and S phases (Hosokawa et al 1995, Karsunky et al 1999, Geisen et al 2003, Kang-Decker et al 2004); however, we observed an increase only in the mRNA expression of cyclin E in hyperthyroid animals, but we cannot rule out an increment in its protein levels at other time points.…”

Section: Figurementioning

confidence: 99%

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Sterle¹,

Valli²,

Cayrol³

et al. 2014

Journal of Endocrinology

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We have shown in vitro that thyroid hormones (THs) regulate the balance between proliferation and apoptosis of T lymphoma cells. The effects of THs on tumor development have been studied, but the results are still controversial. Herein, we show the modulatory action of thyroid status on the in vivo growth of T lymphoma cells. For this purpose, euthyroid, hypothyroid, and hyperthyroid mice received inoculations of EL4 cells to allow the development of solid tumors. Tumors in the hyperthyroid animals exhibited a higher growth rate, as evidenced by the early appearance of palpable solid tumors and the increased tumor volume. These results are consistent with the rate of cell division determined by staining tumor cells with carboxyfluorescein succinimidyl ester. Additionally, hyperthyroid mice exhibited reduced survival. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. Additionally, only tumors from hyperthyroid animals had increased expression levels of proliferating cell nuclear antigen and active caspase 3. Differential expression of cell cycle regulatory proteins was also observed. The levels of cyclins D1 and D3 were augmented in the tumors of the hyperthyroid animals, whereas the cell cycle inhibitors p16/INK4A (CDKN2A) and p27/Kip1 (CDKN1B) and the tumor suppressor p53 (TRP53) were increased in hypothyroid mice. Intratumoral and peritumoral vasculogenesis was increased only in hyperthyroid mice. Therefore, we propose that the thyroid status modulates the in vivo growth of EL4 T lymphoma through the regulation of cyclin, cyclin-dependent kinase inhibitor, and tumor suppressor gene expression, as well as the stimulation of angiogenesis.

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“…These abnormalities are frequently observed in CTCL, suggesting their early involvement in disease pathogenesis [92,93]. Cyclin upregulation, including cyclinD1, and loss of RB1 have also been described [94]. As gene-expression profiling and nextgeneration sequencing technologies are used, additional pathogenic pathways, including those involving transcription factors regulating T-cell differentiation [35,36], c-MYC [95,96], RAS/RAF/MEK signaling [97], among others [90,98], may be identified in subsets of CTCL.…”

Section: Immunopathogenesismentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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Heterogeneous Abnormalities of CCND1 and RB1 in Primary Cutaneous T-Cell Lymphomas Suggesting Impaired Cell Cycle Control in Disease Pathogenesis

Cited by 35 publications

References 38 publications

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

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