Gain-of-function <i>CCR4</i> mutations in adult T cell leukemia/lymphoma

Nakagawa, Masao; Schmitz, Roland; Xiao, Wenming; Goldman, Carolyn K.; Xu, Weihong; Yang, Yandan; Yu, Xin; Waldmann, Thomas A.; Staudt, Louis M.

doi:10.1084/jem.20140987

Cited by 128 publications

(119 citation statements)

References 32 publications

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“…Overexpression of CCR4 was reported in SS 35 and as a result anti- CCR4 therapy is underway with promising early results in MF/SS patients 35,36 . Recently, gain-of-function, C-terminal CCR4 mutations were reported in 26% of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus-I 37 , which like SS also exhibits “skin-homing” pathophysiology. In our SS cohort, 7% of patients harbored CCR4 somatic mutations and all of them were located at the C-terminus including the recurrent Y331X, Q330X, and 3 novel sites that were not previously reported ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

et al. 2015

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Sézary Syndrome is a rare leukemic form of cutaneous T-cell lymphoma defined as erythroderma, adenopathy, and circulating atypical T-lymphocytes. It is rarely curable with poor prognosis. Here we present a multi-platform genomic analysis of 37 Sézary Syndrome patients that implicates dysregulation of the cell cycle checkpoint and T-cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1, and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly a third of patients. ZEB1, a transcription repressor essential for T-cell differentiation, was deleted in over half of patients. IL32 and IL2RG were over-expressed in nearly all cases. Analysis of T-cell receptor Vβ and Vα expression revealed ongoing rearrangement of the receptors after the expansion of a malignant clone in one third of subjects. Our results demonstrate profound disruption of key signaling pathways in Sézary Syndrome and suggest potential targets for novel therapies.

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Section: Resultsmentioning

confidence: 99%

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

et al. 2015

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“…While not all cytokines implicated in T-cell lymphoma pathogenesis signal via the JAK/STAT pathway(65–68), most cytokines implicated in these lymphomas signal via this conserved pathway, inhibition of which impairs their growth and survival(69–71). While evidence of STAT activation is frequently observed in the T-cell lymphomas, recent whole-genome and whole-exome sequencing studies demonstrate that recurrent mutations in JAK and STAT genes are prevalent in some of these disorders.…”

Section: Signal 3 In T-cell Lymphomasmentioning

confidence: 99%

A three‐signal model of T‐cell lymphoma pathogenesis

Wilcox

2015

American J Hematol

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T-cell lymphoma pathogenesis and classification have, until recently, remained enigmatic. Recently performed whole-exome sequencing and gene-expression profiling studies have significant implications for their classification and treatment. Recurrent genetic modifications in antigen (“signal 1”), costimulatory (“signal 2”), or cytokine receptors (“signal 3”), and the tyrosine kinases and other signaling proteins they activate, have emerged as important therapeutic targets in these lymphomas. Many of these genetic modifications do not function in a cell-autonomous manner, but require the provision of ligand(s) by constituents of the tumor microenvironment, further supporting the long-appreciated view that these lymphomas are dependent upon and driven by their microenvironment. Therefore, the seemingly disparate fields of genomics and immunology are converging. A unifying “3 signal model” for T-cell lymphoma pathogenesis that integrates these findings will be presented, and its therapeutic implications briefly reviewed.

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“…Although the genomic integration site influences clonal proliferation and proviral gene expression[16], it does not appear to explain clonal dominance in most cases of ATL[15]. Spontaneous mutations in the T cell receptor (TCR)/NF-kB[17], CCR4[18], p53[19] and, Notch-1[20] signalling pathways are frequently observed in malignant clones.…”

Section: Introductionmentioning

confidence: 99%

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

et al. 2016

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There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

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Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma

Cited by 128 publications

References 32 publications

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

A three‐signal model of T‐cell lymphoma pathogenesis

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

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