{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T01:34:26Z","timestamp":1793324066174,"version":"4.5.0"},"reference-count":92,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"Norman and Melinda Payson in Hematologic Cancers","doi-asserted-by":"publisher","award":["1P01CA229100-01"],"award-info":[{"award-number":["1P01CA229100-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"Norman and Melinda Payson in Hematologic Cancers","doi-asserted-by":"publisher","award":["1P01CA233412-01A1"],"award-info":[{"award-number":["1P01CA233412-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.<\/jats:p>","DOI":"10.3390\/cancers14153716","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T21:49:02Z","timestamp":1659304142000},"page":"3716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-0654","authenticated-orcid":false,"given":"Xiaoqian","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Hematology, Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyao","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1677-0814","authenticated-orcid":false,"given":"Xuxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6243-6008","authenticated-orcid":false,"given":"Wing C. (John)","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1182\/blood-2016-02-698977","article-title":"Activating Mutations in Genes Related to Tcr Signaling in Angioimmunoblastic and Other Follicular Helper T-Cell-Derived Lymphomas","volume":"128","author":"Vallois","year":"2016","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1158\/1078-0432.CCR-21-0573","article-title":"Genome-Wide Microrna Expression Profiling of Molecular Subgroups of Peripheral T-Cell Lymphoma","volume":"27","author":"Lone","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(05)87001-4","article-title":"Role of the Lat Adaptor in T-Cell Development and Th2 Differentiation","volume":"87","author":"Malissen","year":"2005","journal-title":"Adv. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.tibs.2017.11.008","article-title":"TCR Signaling: Mechanisms of Initiation and Propagation","volume":"43","author":"Courtney","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706","article-title":"T Cell Activation","volume":"27","author":"Koretzky","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.molcel.2013.08.032","article-title":"Structural Architecture of the CARMA1\/BCL10\/MALT1 Signalosome: Nucleation-Induced Filamentous Assembly","volume":"51","author":"Qiao","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1146\/annurev.immunol.20.100301.064807","article-title":"Protein Kinase C\u03b8 in T Cell Activation","volume":"20","author":"Isakov","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nri1248","article-title":"Cd28-Mediated Co-Stimulation: A Quantitative Support for TCR Signalling","volume":"3","author":"Acuto","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.immuni.2016.04.020","article-title":"CD28 Costimulation: From Mechanism to Therapy","volume":"44","author":"Esensten","year":"2016","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.imlet.2014.10.020","article-title":"TCR and CD28 Activate the Transcription Factor NF-\u03baB in T-Cells via Distinct Adaptor Signaling Complexes","volume":"163","author":"Thaker","year":"2015","journal-title":"Immunol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/sj.bjc.6602997","article-title":"Mycosis fungoides: Is It a Borrelia burgdorferi-Associated Disease?","volume":"94","author":"Tothova","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_13","first-page":"509","article-title":"Study of the Immunohistochemistry and T Cell Clonality of Enteropathy-Associated T Cell Lymphoma","volume":"146","author":"Murray","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4890","DOI":"10.1182\/blood-2006-05-022277","article-title":"Monoclonal TCR-V\u03b213.1+\/CD4+\/NKa+\/CD8\u2212\/+dim T-LGL Lymphocytosis: Evidence for an Antigen-Driven Chronic T-Cell Stimulation Origin","volume":"109","author":"Garrido","year":"2007","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s11899-013-0165-2","article-title":"T-Cell Receptor Signaling in Peripheral T-Cell Lymphoma\u2014A Review of Patterns of Alterations in a Central Growth Regulatory Pathway","volume":"8","author":"Warner","year":"2013","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1182\/blood-2003-05-1675","article-title":"Hepatosplenic \u03b3\u03b4T-Cell Lymphoma Is a Rare Clinicopathologic Entity with Poor Outcome: Report on a Series of 21 Patients","volume":"102","author":"Belhadj","year":"2003","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41379-018-0130-7","article-title":"Transcriptional Analysis Distinguishes Breast Implant-Associated Anaplastic Large Cell Lymphoma from Other Peripheral T-Cell Lymphomas","volume":"32","author":"Piccaluga","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e139675","DOI":"10.1172\/JCI139675","article-title":"Chronic T Cell Receptor Stimulation Unmasks NK Receptor Signaling in Peripheral T Cell Lymphomas via Epigenetic Reprogramming","volume":"131","author":"Carras","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ccell.2018.01.001","article-title":"RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis","volume":"33","author":"Cortes","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11301","DOI":"10.1038\/s41598-017-11310-0","article-title":"Assessment of T-Cell Receptor Repertoire and Clonal Expansion in Peripheral T-Cell Lymphoma Using RNA-Seq Data","volume":"7","author":"Gong","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cellsig.2006.09.007","article-title":"The NPM-ALK Tyrosine Kinase Mimics TCR Signalling Pathways, Inducing NFAT and AP-1 by RAS-Dependent Mechanisms","volume":"19","author":"Turner","year":"2007","journal-title":"Cell Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.3324\/haematol.2019.238766","article-title":"Whole Exome Sequencing Reveals NOTCH1 Mutations in Anaplastic Large Cell Lymphoma and Points to Notch Both as a Key Pathway and a Potential Therapeutic Target","volume":"106","author":"Larose","year":"2021","journal-title":"Haematologica"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/ng.3415","article-title":"Integrated Molecular Analysis of Adult T Cell Leukemia\/Lymphoma","volume":"47","author":"Kataoka","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1111\/cas.13303","article-title":"Genetic Alterations in Adult T-Cell Leukemia\/Lymphoma","volume":"108","author":"Kogure","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/ng.2873","article-title":"Recurrent Mutations in Epigenetic Regulators, RHOA and FYN Kinase in Peripheral T Cell Lymphomas","volume":"46","author":"Palomero","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ng.2872","article-title":"Somatic RHOA Mutation in Angioimmunoblastic T Cell Lymphoma","volume":"46","author":"Enami","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/ng.2916","article-title":"A Recurrent Inactivating Mutation in RHOA GTPase in Angioimmunoblastic T Cell Lymphoma","volume":"46","author":"Yoo","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1182\/blood-2017-02-768234","article-title":"Genomic Analysis of 220 CTCLs Identifies a Novel Recurrent Gain-of-Function Alteration in RLTPR (p.Q575E)","volume":"130","author":"Park","year":"2017","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1002\/1521-4141(2000012)30:12<3403::AID-IMMU3403>3.0.CO;2-H","article-title":"Rho Regulates T Cell Receptor ITAM-Induced Lymphocyte Spreading in an Integrin-Independent Manner","volume":"30","author":"Borroto","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/nature13765","article-title":"Loss of Signalling Via G\u03b113 in Germinal Centre B-Cell-Derived Lymphoma","volume":"516","author":"Muppidi","year":"2014","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/leu.2017.273","article-title":"Activation of RHOA-VAV1 Signaling in Angioimmunoblastic T-Cell Lymphoma","volume":"32","author":"Fujisawa","year":"2018","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1182\/blood-2014-02-555946","article-title":"The RHOA G17V Gene Mutation Occurs Frequently in Peripheral T-Cell Lymphoma and Is Associated with a Characteristic Molecular Signature","volume":"123","author":"Manso","year":"2014","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1182\/blood-2017-11-818617","article-title":"RhoA G17V Is Sufficient to Induce Autoimmunity and Promotes T-Cell Lymphomagenesis in Mice","volume":"132","author":"Ng","year":"2018","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3324\/haematol.2020.265991","article-title":"Early Detection of T-Cell Lymphoma with T Follicular Helper Phenotype by RHOA Mutation Analysis","volume":"107","author":"Dobson","year":"2022","journal-title":"Haematologica"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/PAS.0000000000000555","article-title":"Angioimmunoblastic T-Cell Lymphomas with the RHOA, p.Gly17val Mutation Have Classic Clinical and Pathologic Features","volume":"40","author":"Ondrejka","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1111\/pin.12981","article-title":"RHOA Mutation in Follicular T-Cell Lymphoma: Clinicopathological Analysis of 16 Cases","volume":"70","author":"Miyoshi","year":"2020","journal-title":"Pathol. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.clml.2021.03.002","article-title":"Clinicopathological Implications of RHOA Mutations in Angioimmunoblastic T-Cell Lymphoma: A Meta-Analysis: RHOA Mutations in AITL","volume":"21","author":"Nguyen","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1080\/10428194.2019.1702179","article-title":"Angioimmunoblastic T-Cell Lymphoma in Taiwan Reveals Worse Progression-Free Survival for RHOA G17V Mutated Subtype","volume":"61","author":"Hsu","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_39","first-page":"1466","article-title":"A Comprehensive Analysis of RHOA Mutation Positive and Negative Angioimmunoblastic T-Cell Lymphomas by Targeted Deep Sequencing, Expression Profiling and Single Cell Digital Image Analysis","volume":"46","author":"Butzmann","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S0960-9822(98)70224-6","article-title":"Vav Is a Regulator of Cytoskeletal Reorganization Mediated by the T-Cell Receptor","volume":"8","author":"Fischer","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/374474a0","article-title":"Defective T-Cell Receptor Signalling and Positive Selection of Vav-Deficient Cd4+ Cd8+ Thymocytes","volume":"374","author":"Fischer","year":"1995","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1182\/blood-2016-03-707141","article-title":"Integrated Mate-Pair and Rna Sequencing Identifies Novel, Targetable Gene Fusions in Peripheral T-Cell Lymphoma","volume":"128","author":"Boddicker","year":"2016","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1182\/blood.2020006513","article-title":"VAV1 Mutations Contribute to Development of T-Cell Neoplasms in Mice","volume":"136","author":"Fukumoto","year":"2020","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1073\/pnas.1608839114","article-title":"Activating Mutations and Translocations in the Guanine Exchange Factor VAV1 in Peripheral T-Cell Lymphomas","volume":"114","author":"Abate","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1038\/s41375-019-0473-1","article-title":"Molecular Heterogeneity in Peripheral T-Cell Lymphoma, Not Otherwise Specified Revealed by Comprehensive Genetic Profiling","volume":"33","author":"Watatani","year":"2019","journal-title":"Leukemia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.cell.2009.12.033","article-title":"Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1","volume":"140","author":"Yu","year":"2010","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1182\/blood-2020-143052","article-title":"VAV1-GFP Fusion Protein Generated by Intron-Based Genome Editing through Crispr\/Cas9 Leads to Spontaneous Activation in TCR Signaling","volume":"136","author":"Liu","year":"2020","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1200\/JCO.2013.52.0924","article-title":"Multicenter Phase Ii Study of Mogamulizumab (Kw-0761), a Defucosylated Anti-Cc Chemokine Receptor 4 Antibody, in Patients with Relapsed Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma","volume":"32","author":"Ogura","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1182\/blood.2019000779","article-title":"Reproducing the Molecular Subclassification of Peripheral T-Cell Lymphoma-NOS by Immunohistochemistry","volume":"134","author":"Amador","year":"2019","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7990","DOI":"10.1038\/sj.onc.1208074","article-title":"Function of the Src-Family Kinases, Lck and Fyn, in T-Cell Development and Activation","volume":"23","author":"Palacios","year":"2004","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s43018-020-00161-w","article-title":"FYN-TRAF3IP2 Induces NF-\u03baB Signaling-Driven Peripheral T Cell Lymphoma","volume":"2","author":"Moon","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1074\/jbc.M209677200","article-title":"BMS-345541 Is a Highly Selective Inhibitor of I\u03baB Kinase That Binds at an Allosteric Site of the Enzyme and Blocks NF-\u03baB-Dependent Transcription in Mice","volume":"278","author":"Burke","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.bmcl.2005.09.035","article-title":"Design and Preparation of 2-Benzamido-Pyrimidines as Inhibitors of Ikk","volume":"16","author":"Waelchli","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/sj.leu.2404045","article-title":"Novel T(5;9)(Q33;Q22) Fuses ITK to SYK in Unspecified Peripheral T-Cell Lymphoma","volume":"20","author":"Streubel","year":"2006","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.jmoldx.2021.04.013","article-title":"Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay","volume":"23","author":"Drieux","year":"2021","journal-title":"J. Mol. Diagn."},{"key":"ref_56","first-page":"1077","article-title":"Genome Profiling Revealed the Activation of IL2RG\/JAK3\/STAT5 in Peripheral T-cell Lymphoma Expressing the ITK-SYK Fusion Gene","volume":"55","author":"Zhang","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nature24649","article-title":"PD-1 Is a Haploinsufficient Suppressor of T Cell Lymphomagenesis","volume":"552","author":"Wartewig","year":"2017","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.bbrc.2018.09.019","article-title":"Translocation-Generated ITK-FER and ITK-SYK Fusions Induce STAT3 Phosphorylation and CD69 Expression","volume":"504","author":"Fathi","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1182\/blood-2018-99-119944","article-title":"The Novel SYK\/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed\/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma","volume":"132","author":"Horwitz","year":"2018","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1182\/blood-2013-05-504308","article-title":"PLCG1 Mutations in Cutaneous T-Cell Lymphomas","volume":"132","author":"Vaque","year":"2014","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1111\/cas.14806","article-title":"Genetic Profile of Adult T-Cell Leukemia\/Lymphoma in Okinawa: Association with Prognosis, Ethnicity, and Htlv-1 Strains","volume":"112","author":"Sakihama","year":"2021","journal-title":"Cancer Sci"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1038\/jid.2015.161","article-title":"PLCG1 Gene Mutations Are Uncommon in Cutaneous T-Cell Lymphomas","volume":"135","author":"Caumont","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jid.2019.07.693","article-title":"Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC\u03b31 Activity and Stimulate NF\u03baB, AP-1, and NFAT Signaling","volume":"140","author":"Patel","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ccell.2015.03.006","article-title":"Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma","volume":"27","author":"Crescenzo","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1084\/jem.20160894","article-title":"Enteropathy-Associated T Cell Lymphoma Subtypes Are Characterized by Loss of Function of SETD2","volume":"214","author":"Moffitt","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/ng.3358","article-title":"Exome Sequencing Identifies Somatic Mutations of DDX3X in Natural Killer\/T-Cell Lymphoma","volume":"47","author":"Jiang","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cell.2010.12.013","article-title":"Crystal Structure and Allosteric Activation of Protein Kinase C \u03b2II","volume":"144","author":"Leonard","year":"2011","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"a003004","DOI":"10.1101\/cshperspect.a003004","article-title":"Antigen Receptor Signaling to NF-\u03baB-Via CARMA1, BCL10, and MALT1","volume":"2","author":"Thome","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.molimm.2015.07.024","article-title":"TCR Signaling to NF-\u03baB and mTORC1: Expanding Roles of the CARMA1 Complex","volume":"68","author":"Shi","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature08638","article-title":"Chronic Active B-Cell-Receptor Signalling in Diffuse Large B-Cell Lymphoma","volume":"463","author":"Davis","year":"2010","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.immuni.2005.09.014","article-title":"Phosphorylation of the CARMA1 Linker Controls NF-\u03baB Activation","volume":"23","author":"Sommer","year":"2005","journal-title":"Immunity"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Yoshida, N., Miyoshi, H., and Ohshima, K. (2021). Clinical Applications of Genomic Alterations in ATLL: Predictive Markers and Therapeutic Targets. Cancers, 13.","DOI":"10.3390\/cancers13081801"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/leu.2015.357","article-title":"Recurrent Activating Mutations of Cd28 in Peripheral T-Cell Lymphomas","volume":"30","author":"Rohr","year":"2016","journal-title":"Leukemia"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/mgg3.121","article-title":"Personalized Treatment of S\u00e9zary Syndrome by Targeting a Novel CTLA4:CD28 Fusion","volume":"3","author":"Sekulic","year":"2015","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/ng.3370","article-title":"Genomic Analysis of Mycosis Fungoides and S\u00e9zary Syndrome Identifies Recurrent Alterations in Tnfr2","volume":"47","author":"Ungewickell","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e505","DOI":"10.3324\/haematol.2015.133074","article-title":"A Highly Recurrent Novel Missense Mutation in CD28 among Angioimmunoblastic T-Cell Lymphoma Patients","volume":"100","author":"Lee","year":"2015","journal-title":"Haematologica"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"757","DOI":"10.3324\/haematol.2015.139253","article-title":"Frequent CTLA4-CD28 Gene Fusion in Diverse Types of T-Cell Lymphoma","volume":"101","author":"Yoo","year":"2016","journal-title":"Haematologica"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e269","DOI":"10.3324\/haematol.2016.147074","article-title":"Comment on Yoo et al. Frequent CTLA4-CD28 Gene Fusion in Diverse Types of T-Cell Lymphoma","volume":"101","author":"Gong","year":"2016","journal-title":"Haematologica"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1600-065X.2009.00770.x","article-title":"CD28 and CTLA-4 Coreceptor Expression and Signal Transduction","volume":"229","author":"Rudd","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1182\/blood-2018-09-872549","article-title":"Genetic Drivers of Oncogenic Pathways in Molecular Subgroups of Peripheral T-Cell Lymphoma","volume":"133","author":"Heavican","year":"2019","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1126\/science.1150799","article-title":"The Structure of a Human P110\u03b1\/P85\u03b1 Complex Elucidates the Effects of Oncogenic PI3K\u03b1 Mutations","volume":"318","author":"Huang","year":"2007","journal-title":"Science"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3330","article-title":"The Functions and Regulation of the PTEN Tumour Suppressor","volume":"13","author":"Song","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41580-018-0015-0","article-title":"The Functions and Regulation of the PTEN Tumour Suppressor: New Modes and Prospects","volume":"19","author":"Lee","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7418","DOI":"10.1158\/0008-5472.CAN-14-1420","article-title":"Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma","volume":"74","author":"Chinen","year":"2014","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1182\/blood-2017-08-802470","article-title":"Activity of the PI3K-\u03b4, \u03b3 Inhibitor Duvelisib in a Phase 1 Trial and Preclinical Models of T-Cell Lymphoma","volume":"131","author":"Horwitz","year":"2018","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Huen, A., Haverkos, B.M., Zain, J., Radhakrishnan, R., Lechowicz, M.J., Devata, S., Korman, N.J., Pinter-Brown, L., Oki, Y., and Barde, P.J. (2020). Phase I\/Ib Study of Tenalisib (Rp6530), a Dual PI3K \u03b4\/\u03b3 Inhibitor in Patients with Relapsed\/Refractory T-Cell Lymphoma. Cancers, 12.","DOI":"10.3390\/cancers12082293"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1182\/blood-2013-11-536359","article-title":"Gene Expression Signatures Delineate Biological and Prognostic Subgroups in Peripheral T-Cell Lymphoma","volume":"123","author":"Iqbal","year":"2014","journal-title":"Blood"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3960\/jslrt.20059","article-title":"Molecular Understanding of Peripheral T-Cell Lymphomas, Not Otherwise Specified (PTCL, NOS): A Complex Disease Category","volume":"61","author":"Fukumoto","year":"2021","journal-title":"J. Clin. Exp. Hematop."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"151623","DOI":"10.1016\/j.anndiagpath.2020.151623","article-title":"American Registry of Pathology Expert Opinions: Recommendations for the Diagnostic Workup of Mature T Cell Neoplasms","volume":"49","author":"Vega","year":"2020","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1111\/bjh.15702","article-title":"Phase I\/II Study of Dasatinib and Exploratory Genomic Analysis in Relapsed or Refractory Non-Hodgkin Lymphoma","volume":"184","author":"Umakanthan","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1182\/blood-2017-01-761874","article-title":"Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia\/Lymphoma","volume":"131","author":"Kataoka","year":"2018","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/cas.15191","article-title":"Clinicopathological Significance of CD28 Overexpression in Adult T-Cell Leukemia\/Lymphoma","volume":"113","author":"Sakamoto","year":"2022","journal-title":"Cancer Sci."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3716\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:59:37Z","timestamp":1760140777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3716"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,29]]},"references-count":92,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cancers14153716"],"URL":"https:\/\/doi.org\/10.3390\/cancers14153716","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,29]]}}}