Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

Palomero, Teresa; Couronné, Lucile; Khiabanian, Hossein; Kim, Mi‐Yeon; Ambesi-Impiombato, Alberto; Pérez-García, Arianne; Carpenter, Zachary; Abate, Francesco; Allegretta, Maddalena; Haydu, J. Erika; Jiang, Xiaoyu; Lossos, Izidore S.; Nicolas, Concha; Balbı́n, Milagros; Bastard, Christian; Bhagat, Govind; Piris, Miguel Á.; Campo, Elı́as; Bernard, Olivier A.; Rabadán, Raúl; Ferrando, Adolfo A.

doi:10.1038/ng.2873

Cited by 528 publications

(653 citation statements)

References 38 publications

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“…In AITL, PTCL-NOS and CTCL subtypes, DNMT3A mutations cluster in the methyltransferase domain. Interestingly, only about 20% of these mutations are at position R882 [75,77,94,95,97], the variant commonly found in myeloid diseases acting as a negatively regulating hypomorphic protein [105]. Dnm3a -deficient mice develop a PTCL-like disease at a frequency of 12% and heterozygous animals at a rate of 10%, associated with hypomethylation and decreased TP53 activity [106].…”

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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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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“…Les mutations de TET2 sont observées chez environ 60 à 70 % des patients [22][23][24][25][26][27] et 2 de ces mutations sont présentes dans presque la moitié des cas [22,23]. Elles sont réparties sur la totalité du gène et sont de nature inactivatrice (mutations des sites d'épissage, mutations non-sens, faux-sens dans des régions conservées dans l'évolution).…”

Section: Mutations Ponctuelles Observées Dans Les Laitunclassified

“…Elles sont réparties sur la totalité du gène et sont de nature inactivatrice (mutations des sites d'épissage, mutations non-sens, faux-sens dans des régions conservées dans l'évolution). Les mutations de DNMT3A surviennent chez 20 à 30 % des patients et sont quasiment toujours associées aux mutations de TET2 [23][24][25]27]. IDH2 est muté au niveau du codon R172 chez 20 à 30 % des patients [22,25,28], et ces mutations sont souvent associées à celles de TET2 [22,23].…”

Section: Mutations Ponctuelles Observées Dans Les Laitunclassified

“…Les mutations d'IDH2 ont pour effet d'inhiber indirectement les oxydases dépendantes du 2-oxoglutarate et du fer, telles que les protéines de la famille TET [29]. Une mutation récurrente du gène RHOA (G17V) est observée chez environ 70 % des patients [24,25,30]. Elle est fréquemment associée aux mutations de TET2 et de DNMT3A [24,25].…”

Section: Mutations Ponctuelles Observées Dans Les Laitunclassified

“…Une mutation récurrente du gène RHOA (G17V) est observée chez environ 70 % des patients [24,25,30]. Elle est fréquemment associée aux mutations de TET2 et de DNMT3A [24,25]. La protéine RHOA fait partie de la famille des petites GTPases qui passent d'un état inactif lié au GDP à un état actif lié au GTP.…”

Section: Mutations Ponctuelles Observées Dans Les Laitunclassified

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Molecular Genetics of Peripheral T‐c ell Lymphomas

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Peripheral T‐cell lymphomas (PTCLs) are rare neoplasms constituting a heterogeneous group of diseases. Recent studies based on high‐throughput technologies (including DNA microarray and deep sequencing) offered several evidences that discrete subgroups can be identified with peculiar molecular and clinical features. In this regard, gene expression profiling (GEP) analyses demonstrated that the commonest nodal PTCL subtypes (not otherwise specified, NOS; angioimmunoblastic, AITL; anaplastic large cell lymphoma, ALCL) can be efficiently diagnosed based on the expression of a few genes. Noteworthy, the molecular diagnosis of nodal PTCLs turned out to be more efficient than histopathology in providing an accurate prognostic stratification. In addition, GEP indicated commonly deregulated genes and pathways, including tyrosine kinase signalling, NFkB pathway, angiogenesis and chromatin remodelling, which may represent suitable therapeutics targets. Finally, sequencing studies recently identified new lesions associated with specific PTCL subtypes, such as IDH2, TET2 and RHOA mutations in follicular helper derived cases and t(6;9) in ALK‐ ALCL. In this article, we review the available literature on genetics of PTCLs and, also based on our own experience, discuss prospective scenarios on this intriguing topic. Key Concepts The molecular genetics of peripheral T‐cell lymphomas is, with a few exceptions, poorly known. Gene expression profiling studies provided evidences of molecular differences among subtypes and recognised commonly deregulated genes and pathways that may represent suitable therapeutic targets. High‐throughput sequencing studies are ongoing and will further clarify the genetic basis of these complex diseases.

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Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

Cited by 528 publications

References 38 publications

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

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

Aspects moléculaires des lymphomes T périphériques (1)

Molecular Genetics of Peripheral T‐c ell Lymphomas

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