Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis

Schatz, Jonathan H.; Horwitz, Sarah M.; Teruya‐Feldstein, Julie; Lunning, Matthew A.; Viale, Agnès; Huberman, Kety; Socci, Nicholas D.; Lailler, Nathalie; Heguy, Adriana; Dolgalev, Igor; Migliacci, Jocelyn; Pirun, Mono; Palomba, Martina; Weinstock, David M.; Wendel, Hans Guido

doi:10.1038/leu.2014.261

Cited by 68 publications

(68 citation statements)

References 14 publications

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“…83 In addition, recent studies in both CTCL and PTCL have shown mutations of ARID1A/B involved in chromatin remodeling. 3,84 These findings suggest that chromatin modification plays a key role in malignant transformation of mature T cells as recently described for B-cell non-Hodgkin lymphoma. 85 Analysis of our data sets revealed that 42% of the C.T variants occurred at NpCpG sites, which could be consistent with at least 5 of 21 recently described signatures including age-related deamination of methylated cytosines.…”

Section: R757cmentioning

confidence: 62%

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Woollard

Pullabhatla

Lorenc

et al. 2016

Blood

101

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Section: R757cmentioning

confidence: 62%

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Woollard

Pullabhatla

Lorenc

et al. 2016

Blood

101

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“…[7, 22, 23] Loss of function mutations in KMT2D / MLL2 , a lysine specific histone methyltransferase targeting H3K4 residues that is considered to function as a tumor suppressor, have been reported in PTCL arising in immunocompetent individuals and were seen in a variety of T/NK-PTLD. [24] Missense mutations in TET2 , a methylcytosine dioxygenase that plays an important role in active DNA demethylation, are frequent in both PTCL, NOS and AITL (38% and 33-76%, respectively). [23, 25, 26] Loss of function mutations in DNMT3A , a DNA methyltransferase that is required for genome-wide de novo methylation, are frequent in a variety of malignancies and have been reported in up to 38% of PTCL, NOS and 33%-37% AITL.…”

Section: Discussionmentioning

confidence: 99%

“…[29] Mutations in chromatin modifier genes, including ARID1B , and ARID2 , were also common, a finding in line with prior studies of PTCL occurring in immunocompetent hosts. [24]…”

Section: Discussionmentioning

confidence: 99%

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

et al. 2016

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Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.

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“…Moreover, TCR activation was linked to PTCL-NOS with the ITK-SYK fusion gene being present in approximately 10% of cases [52,71], or MYC overexpression due to IRF4 activating fusions [72] mimicking survival signals normally emanating from antigen receptor signaling. Furthermore, missense mutations in TNFAIP3 , encoding the negative regulator of NF-κB activation A20 in T-cells after TCR stimulation [73], mutations in WNT/β-Catenin negative regulators APC and CHD8 , and other genes with known suppressive roles in TCR activation were disease associated [74]. GATA3 and TBX21 expression are both important in T-cell development, and mutations in these genes may be associated with the PTCL-NOS subgroups, representing potential diagnostic predictors and possibly also therapeutic targets [59].…”

Section: Targets In Ptcl and Driver Mutationsmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis

Cited by 68 publications

References 14 publications

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

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