Characterization of the DNA Copy-Number Genome in the Blood of Cutaneous T-Cell Lymphoma Patients

Lin, William M.; Lewis, Julia M.; Filler, Renata; Modi, Badri; Carlson, Kacie R.; Reddy, Swapna; Thornberg, Adam; Saksena, Gordon; Umlauf, Sheila; Oberholzer, Patrick A.; Karpova, Maria B.; Getz, Gad; Mane, Shrikant; Garraway, Levi A.; Dummer, Reinhard; Berger, Carole L.; Edelson, Richard L.; Girardi, Michael

doi:10.1038/jid.2011.254

Cited by 39 publications

(33 citation statements)

References 35 publications

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“…4a). This gain correlated with increased TNFRSF1B transcript levels in patient tumor samples and with increased TNFR2 protein levels in the HH CTCL cell line that harbors this gain 18 (Fig. 3c–e and Supplementary Fig.…”

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confidence: 76%

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

et al. 2015

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Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized1. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-ºB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

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confidence: 76%

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

et al. 2015

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“…In CTCL, various cytogenetic studies found multiple genetic alterations that recur in a subset of mycosis fungoides and/or S ezary syndrome patients (36)(37)(38). But few common genetic variants including targetable mutations have been identified (39).…”

Section: Discussionmentioning

confidence: 99%

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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Purpose: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergence of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic antiproliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL.Experimental Design: The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/propidium iodide (PI) apoptosis assay in different CTCL cell lines and tumor cells derived from S ezary syndrome patients. Quantitative analysis of a dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays, and chromatin immunoprecipitation. Global CpG methylation sequencing was utilized to study genome methylation alteration under the treatment modalities.Results: The combination of romidepsin and azacitidine exerts synergistic antiproliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines and tumor cells derived from S ezary syndrome patients. We identified genes that were selectively induced by the combination treatment, such as the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment.Conclusions: The synergistic antiproliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL.

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“…Early cytogenetic studies in CTCL revealed some alterations associated with shorter survival, such as gain of 8q (including MYC) and losses of 6q and 13q (including RB), 17p (TP53), 10 (PTEN, FAS), and 9p21 deletion (including CDKN2A). [16][17][18][19][20] Some of these chromosomal alterations are common to MF and SS, whereas others are more specific, such as gain of chr7 and loss of 9p21 in MF, or gain of 8q and 17q and loss of 10q and 17p in SS. 16,21,22 Massive parallel sequencing technology is a powerful means of better understanding the genetic basis of tumorigenesis and has helped identify new genetic alterations in solid tumors and other hematological malignancies, such as acute myeloid leukemia, [23][24][25] diffuse large B-cell lymphoma, 26,27 Burkitt lymphoma, 28 chronic lymphocytic leukemia, 29,30 and myelodysplastic syndrome.…”

Section: Introductionmentioning

confidence: 99%

PLCG1 mutations in cutaneous T-cell lymphomas

Vaqué

Gómez‐López

Monsálvez

et al. 2014

Blood

202

199

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Key Points• Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor kB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation. (Blood. 2014;123(13):2034-2043

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Characterization of the DNA Copy-Number Genome in the Blood of Cutaneous T-Cell Lymphoma Patients

Cited by 39 publications

References 35 publications

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

PLCG1 mutations in cutaneous T-cell lymphomas

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