Pizzi, M., Margolskee, E. & Inghirami, G. Pathogenesis of peripheral T cell lymphoma. Annu. Rev. Pathol. 13, 293–320 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Fiore, D. et al. Peripheral T cell lymphomas: from the bench to the clinic. Nat. Rev. Cancer 20, 323–342 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

World Health Organization. Haematolymphoid Tumours 5th edn, Vol. 11 (WHO, 2024).

Cortés, J. R. & Palomero, T. Biology and molecular pathogenesis of mature T-cell lymphomas. Cold Spring Harb. Perspect. Med. 11, a035402 (2021).

Article 
PubMed 
PubMed Central 

Google Scholar
 

de Leval, L. et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109, 4952–4963 (2007).

Article 
PubMed 

Google Scholar
 

Bishop, D. C. et al. Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood 138, 1504–1509 (2021). This study, together with Harrison et al. (2023), Kobbe et al. (2024), Braun et al. (2025) and Perica et al. (2025), identified T cell lymphomas that originated from CAR T cells.

Article 
CAS 
PubMed 

Google Scholar
 

Harrison, S. J. et al. CAR plus T-cell lymphoma post ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. Blood 142, 6939 (2023).

Article 

Google Scholar
 

Harrison, S. J. et al. CAR+ T-cell lymphoma after cilta-cel therapy for relapsed or refractory myeloma. N. Engl. J. Med. 392, 677–685 (2025).

Article 
CAS 
PubMed 

Google Scholar
 

Kobbe, G. et al. Aggressive lymphoma after CD19 CAR T-cell therapy. N. Engl. J. Med. 391, 1217–1226 (2024).

Article 
CAS 
PubMed 

Google Scholar
 

Teras, L. R. et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J. Clin. 66, 443–459 (2016).

PubMed 

Google Scholar
 

Liu, S. et al. Epidemiological characteristics of peripheral T-cell lymphoma: a population-based study. Front. Oncol. 12, 863269 (2022).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Dustin, M. L. The immunological synapse. Cancer Immunol. Res. 2, 1023–1033 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Rodilla-Ramirez, C. et al. T cell protrusions enable fast, localised initiation of CAR signalling. Preprint at bioRxiv https://doi.org/10.1101/2025.07.08.662959v1 (2025).

De Boer, R. J., Homann, D. & Perelson, A. S. Different dynamics of CD4+ and CD8+ T cell responses during and after acute lymphocytic choriomeningitis virus infection. J. Immunol. 171, 3928–3935 (2003).

Article 
PubMed 

Google Scholar
 

Bretscher, P. A. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc. Natl Acad. Sci. USA 96, 185–190 (1999).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

Article 
CAS 
PubMed 

Google Scholar
 

Curtsinger, J. M., Gerner, M. Y., Lins, D. C. & Mescher, M. F. Signal 3 availability limits the CD8 T cell response to a solid tumor. J. Immunol. 178, 6752–6760 (2007).

Article 
CAS 
PubMed 

Google Scholar
 

Gaud, G., Lesourne, R. & Love, P. E. Regulatory mechanisms in T cell receptor signalling. Nat. Rev. Immunol. 18, 485–497 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Shah, K., Al-Haidari, A., Sun, J. & Kazi, J. U. T cell receptor (TCR) signaling in health and disease. Signal. Transduct. Target. Ther. 6, 412 (2021).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Davis, S. J. & van der Merwe, P. A. The kinetic-segregation model: TCR triggering and beyond. Nat. Immunol. 7, 803–809 (2006).

Article 
CAS 
PubMed 

Google Scholar
 

Weiss, A. Peeking into the black box of T cell receptor signaling. Annu. Rev. Immunol. 42, 1–20 (2024).

Article 
CAS 
PubMed 

Google Scholar
 

Burkhardt, A. L. et al. Temporal regulation of non-transmembrane protein tyrosine kinase enzyme activity following T cell antigen receptor engagement. J. Biol. Chem. 269, 23642–23647 (1994).

Article 
CAS 
PubMed 

Google Scholar
 

Iwashima, M., Irving, B. A., van Oers, N. S., Chan, A. C. & Weiss, A. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136–1139 (1994).

Article 
CAS 
PubMed 

Google Scholar
 

Chan, A. C., Iwashima, M., Turck, C. W. & Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71, 649–662 (1992).

Article 
CAS 
PubMed 

Google Scholar
 

Balagopalan, L., Coussens, N. P., Sherman, E., Samelson, L. E. & Sommers, C. L. The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harb. Perspect. Biol. 2, a005512 (2010).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Lo, W. L. et al. Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nat. Immunol. 19, 733–741 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wu, J., Motto, D. G., Koretzky, G. A. & Weiss, A. Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation. Immunity 4, 593–602 (1996).

Article 
CAS 
PubMed 

Google Scholar
 

Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83–92 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

Bogin, Y., Ainey, C., Beach, D. & Yablonski, D. SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK. Proc. Natl Acad. Sci. USA 104, 6638–6643 (2007).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Granja, C., Lin, L. L., Yunis, E. J., Relias, V. & Dasgupta, J. D. PLCγ1, a possible mediator of T cell receptor function. J. Biol. Chem. 266, 16277–16280 (1991).

Article 
CAS 
PubMed 

Google Scholar
 

Bunnell, S. C. et al. Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J. Biol. Chem. 275, 2219–2230 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

Scharenberg, A. M. & Kinet, J. P. PtdIns-3,4,5-P3: a regulatory nexus between tyrosine kinases and sustained calcium signals. Cell 94, 5–8 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

Clipstone, N. A. & Crabtree, G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992).

Article 
CAS 
PubMed 

Google Scholar
 

Monks, C. R., Kupfer, H., Tamir, I., Barlow, A. & Kupfer, A. Selective modulation of protein kinase C-Θ during T-cell activation. Nature 385, 83–86 (1997).

Article 
CAS 
PubMed 

Google Scholar
 

Carrasco, S. & Merida, I. Diacylglycerol-dependent binding recruits PKCθ and RasGRP1 C1 domains to specific subcellular localizations in living T lymphocytes. Mol. Biol. Cell 15, 2932–2942 (2004).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Acuto, O. & Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat. Rev. Immunol. 3, 939–951 (2003).

Article 
CAS 
PubMed 

Google Scholar
 

Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

Vander Haar, E., Lee, S. I., Bandhakavi, S., Griffin, T. J. & Kim, D. H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323 (2007).

Article 

Google Scholar
 

Boomer, J. S. & Green, J. M. An enigmatic tail of CD28 signaling. Cold Spring Harb. Perspect. Biol. 2, a002436 (2010).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

Article 
CAS 
PubMed 

Google Scholar
 

Yoshinaga, S. K. et al. Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. Int. Immunol. 12, 1439–1447 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

Rudd, C. E. & Schneider, H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat. Rev. Immunol. 3, 544–556 (2003).

Article 
CAS 
PubMed 

Google Scholar
 

Zola, H. et al. CD molecules 2005: human cell differentiation molecules. Blood 106, 3123–3126 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Schober, T. et al. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat. Commun. 8, 14209 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Bidere, N. et al. Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009).

Article 
CAS 
PubMed 

Google Scholar
 

Ruland, J. & Hartjes, L. CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat. Rev. Immunol. 19, 118–134 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lin, J. T. et al. Naive CD4 T cell proliferation is controlled by mammalian target of rapamycin regulation of GRAIL expression. J. Immunol. 182, 5919–5928 (2009).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sun, L., Su, Y., Jiao, A., Wang, X. & Zhang, B. T cells in health and disease. Signal. Transduct. Target. Ther. 8, 235 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Xue, C. et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal. Transduct. Target. Ther. 8, 204 (2023).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Iida, T. et al. Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4+ T cells. J. Immunol. 165, 5062–5068 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lotze, M. T., Olejniczak, S. H. & Skokos, D. CD28 co-stimulation: novel insights and applications in cancer immunotherapy. Nat. Rev. Immunol. 24, 878–895 (2024).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Yokosuka, T. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209, 1201–1217 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sheppard, K. A. et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004).

Article 
CAS 
PubMed 

Google Scholar
 

Rowshanravan, B., Halliday, N. & Sansom, D. M. CTLA-4: a moving target in immunotherapy. Blood 131, 58–67 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Collins, A. V. et al. The interaction properties of costimulatory molecules revisited. Immunity 17, 201–210 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Hedrick, S. M., Cohen, D. I., Nielsen, E. A. & Davis, M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–153 (1984).

Article 
CAS 
PubMed 

Google Scholar
 

Yanagi, Y. et al. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984).

Article 
CAS 
PubMed 

Google Scholar
 

Minden, M. D. & Mak, T. W. The structure of the T cell antigen receptor genes in normal and malignant T cells. Blood 68, 327–336 (1986).

Article 
CAS 
PubMed 

Google Scholar
 

Liu, X., Ning, J., Liu, X. & Chan, W. C. J. Mutations affecting genes in the proximal T-cell receptor signaling pathway in peripheral T-cell lymphoma. Cancers 14, 3716 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Streubel, B., Vinatzer, U., Willheim, M., Raderer, M. & Chott, A. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 20, 313–318 (2006). This study reported the first gene fusions involving a regulator of TCR signalling in T-NHL.

Article 
CAS 
PubMed 

Google Scholar
 

Attygalle, A. D., Feldman, A. L. & Dogan, A. ITK/SYK translocation in angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 37, 1456–1457 (2013).

Article 
PubMed 

Google Scholar
 

Pechloff, K. et al. The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J. Exp. Med. 207, 1031–1044 (2010). This study was the first to show that enforced oncogenic signalling within TCR pathways can drive T-NHL formation in vivo.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Dierks, C. et al. The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. Cancer Res. 70, 6193–6204 (2010).

Article 
CAS 
PubMed 

Google Scholar
 

Debackere, K. et al. Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified. Nat. Commun. 12, 3705 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lemonnier, F. et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120, 1466–1469 (2012).

Article 
CAS 
PubMed 

Google Scholar
 

Moon, C. S. et al. FYN-TRAF3IP2 induces NF-κB signaling-driven peripheral T cell lymphoma. Nat. Cancer 2, 98–113 (2021). This study determined the mechanism of the FYN–TRAF3IP2 oncogenic fusion in T-NHL and its effect on TCR signalling pathways.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014). This study, together with Yoo et al. (2014) and Nagata et al. (2016), identified the recurrent RHOA G17V hotspot mutation in human T-NHL.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Kataoka, K. et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 47, 1304–1315 (2015). This study defined the genomic landscapes of ATLL and reported numerous gain-of-function alterations in TCR and co-receptor pathways.

Article 
CAS 
PubMed 

Google Scholar
 

Tybulewicz, V. L., Ardouin, L., Prisco, A. & Reynolds, L. F. Vav1: a key signal transducer downstream of the TCR. Immunol. Rev. 192, 42–52 (2003).

Article 
CAS 
PubMed 

Google Scholar
 

Chrencik, J. E. et al. Structural basis of guanine nucleotide exchange mediated by the T-cell essential Vav1. J. Mol. Biol. 380, 828–843 (2008).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Fischer, K. D. et al. Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr. Biol. 8, 554–562 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

Morrish, E. et al. The fusion oncogene VAV1-MYO1F triggers aberrant T-cell receptor signaling in vivo and drives peripheral T-cell lymphoma in mice. Eur. J. Immunol. 53, e2250147 (2023). This study, together with Cortes et al. (2022), showed that the VAV1–MYO1F fusion activates TCR signalling and drives T-NHL in vivo.

Article 
PubMed 

Google Scholar
 

Abate, F. et al. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc. Natl Acad. Sci. USA 114, 764–769 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Fujisawa, M. et al. Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia 32, 694–702 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Cortes, J. R. et al. Oncogenic Vav1-Myo1f induces therapeutically targetable macrophage-rich tumor microenvironment in peripheral T cell lymphoma. Cell Rep. 39, 110695 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Margolis, B. et al. Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. Nature 356, 71–74 (1992).

Article 
CAS 
PubMed 

Google Scholar
 

Crespo, P., Schuebel, K. E., Ostrom, A. A., Gutkind, J. S. & Bustelo, X. R. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product. Nature 385, 169–172 (1997).

Article 
CAS 
PubMed 

Google Scholar
 

Han, J. et al. Lck regulates Vav activation of members of the Rho family of GTPases. Mol. Cell Biol. 17, 1346–1353 (1997).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Yoo, H. Y. et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

Cortes, J. R. et al. RHOA G17V induces T follicular helper cell specification and promotes lymphomagenesis. Cancer Cell 33, 259–273.e7 (2018). This study provided in vivo evidence that RHOA G17V disrupts T cell differentiation and promotes T-NHL development.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Zhang, B. & Zheng, Y. Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1. Biochemistry 37, 5249–5257 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

Zhang, B., Chernoff, J. & Zheng, Y. Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA. J. Biol. Chem. 273, 8776–8782 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

Zhang, Y., Cheng, K. & Choi, J. TCR pathway mutations in mature T cell lymphomas. J. Immunol. 211, 1450–1458 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Robles-Valero, J. et al. Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis. EMBO J. 40, e108125 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Nagata, Y. et al. Variegated RHOA mutations in adult T-cell leukemia/lymphoma. Blood 127, 596–604 (2016).

Article 
CAS 
PubMed 

Google Scholar
 

Park, J. et al. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 130, 1430–1440 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Leca, J. et al. IDH2 and TET2 mutations synergize to modulate T follicular helper cell functional interaction with the AITL microenvironment. Cancer Cell 41, 323–339.e10 (2023).

Article 
CAS 
PubMed 

Google Scholar
 

Stone, E. L. et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42, 239–251 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Zang, S. et al. Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis. J. Clin. Invest. 127, 2998–3012 (2017).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Patel, V. M. et al. Frequent and persistent PLCG1 mutations in Sézary cells directly enhance PLCγ1 activity and stimulate NFκB, AP-1, and NFAT signaling. J. Invest. Dermatol. 140, 380–389.e4 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

Nicolae, A. et al. Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations. Mod. Pathol. 35, 1126–1136 (2022).

Article 
CAS 
PubMed 

Google Scholar
 

Gresset, A., Hicks, S. N., Harden, T. K. & Sondek, J. Mechanism of phosphorylation-induced activation of phospholipase C-γ isozymes. J. Biol. Chem. 285, 35836–35847 (2010).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Vaque, J. P. et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 123, 2034–2043 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

Wang, L. et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat. Genet. 47, 1426–1434 (2015). This study, together with Choi et al. (2015) and da Silva Almeida et al. (2015), characterized the genomic landscapes of CTCL/Sézary syndrome and described multiple alterations in T cell signalling molecules.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Vallois, D. et al. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood 128, 1490–1502 (2016). This study reported the mutational landscapes of TFH cell-derived T-NHL, identifying multiple alterations in TCR and co-receptor signalling molecules.

Article 
CAS 
PubMed 

Google Scholar
 

Coudronniere, N., Villalba, M., Englund, N. & Altman, A. NF-κB activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-θ. Proc. Natl Acad. Sci. USA 97, 3394–3399 (2000).

CAS 
PubMed 
PubMed Central 

Google Scholar
 

Choi, J. et al. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet. 47, 1011–1019 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Watatani, Y. et al. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia 33, 2867–2883 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Garcia-Diaz, N. et al. PLCγ1/PKCθ downstream signaling controls cutaneous T-cell lymphoma development and progression. J. Invest. Dermatol. 142, 1391–1400.e15 (2022).

Article 
CAS 
PubMed 

Google Scholar
 

Kogure, Y. et al. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood 139, 967–982 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Woollard, W. J. et al. Candidate driver genes involved in genome maintenance and DNA repair in Sezary syndrome. Blood 127, 3387–3397 (2016).

Article 
CAS 
PubMed 

Google Scholar
 

Baier-Bitterlich, G. et al. Protein kinase C-θ isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes. Mol. Cell Biol. 16, 1842–1850 (1996).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sekulic, A. et al. Personalized treatment of Sezary syndrome by targeting a novel CTLA4:CD28 fusion. Mol. Genet. Genomic Med. 3, 130–136 (2015). This study identified gain-of-function CTLA4–CD28 co-receptor fusions and demonstrated their responsiveness to ligand inhibition in a patient.

Article 
CAS 
PubMed 

Google Scholar
 

Rohr, J. et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia 30, 1062–1070 (2016).

Article 
CAS 
PubMed 

Google Scholar
 

Yoo, H. Y. et al. Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma. Haematologica 101, 757–763 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Egen, J. G. & Allison, J. P. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16, 23–35 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

Lee, G. J. et al. Mice transgenic for human CTLA4-CD28 fusion gene show proliferation and transformation of ATLL-like and AITL-like T cells. Oncoimmunology 11, 2015170 (2022).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Khayyamian, S. et al. ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. Proc. Natl Acad. Sci. USA 99, 6198–6203 (2002).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Vallois, D. et al. RNA fusions involving CD28 are rare in peripheral T-cell lymphomas and concentrate mainly in those derived from follicular helper T cells. Haematologica 103, e360–e363 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Yoshida, N. et al. Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions. Blood 135, 1467–1471 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Marafioti, T. et al. The inducible T-cell co-stimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation. Haematologica 95, 432–439 (2010).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Amatore, F. et al. ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells. Blood Adv. 4, 5203–5214 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001).

Article 
CAS 
PubMed 

Google Scholar
 

Akiba, H. et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J. Immunol. 175, 2340–2348 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932–946 (2011).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Roncagalli, R. et al. The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells. J. Exp. Med. 213, 2437–2457 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Uchida, Y. et al. RLTPR Q575E: a novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma. Eur. J. Haematol. 106, 221–229 (2021).

Article 
CAS 
PubMed 

Google Scholar
 

da Silva Almeida, A. C. et al. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat. Genet. 47, 1465–1470 (2015).

Article 

Google Scholar
 

Kameda, T. et al. CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma. Commun. Biol. 5, 1309 (2022).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Sommer, K. et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Stinson, J. R. et al. Gain-of-function mutations in CARD11 promote enhanced aggregation and idiosyncratic signalosome assembly. Cell Immunol. 353, 104129 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Garcia, J. et al. Naturally occurring T cell mutations enhance engineered T cell therapies. Nature 626, 626–634 (2024).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

D’Andrea, A. et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J. Exp. Med. 176, 1387–1398 (1992).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Seder, R. A., Paul, W. E., Davis, M. M. & Fazekas de St Groth, B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J. Exp. Med. 176, 1091–1098 (1992).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Matikainen, S. et al. Interferon-α activates multiple STAT proteins and upregulates proliferation-associated IL-2Rα, c-myc, and pim-1 genes in human T cells. Blood 93, 1980–1991 (1999).

Article 
CAS 
PubMed 

Google Scholar
 

Ross, S. H. & Cantrell, D. A. Signaling and function of interleukin-2 in T lymphocytes. Annu. Rev. Immunol. 36, 411–433 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Saraiva, M., Vieira, P. & O’Garra, A. Biology and therapeutic potential of interleukin-10. J. Exp. Med. 217, e20190418 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Fueyo-Gonzalez, F. et al. Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation. Immunity 55, 459–474.e7 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lee, K. et al. Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway. Blood 138, 2435–2440 (2021). This study identified gain-of-function alterations in JAK2–STAT signalling in cytotoxic T cell lymphoma and demonstrated their druggability.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Velusamy, T. et al. A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders. Blood 124, 3768–3771 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

Kuravi, S. et al. Functional characterization of NPM1-TYK2 fusion oncogene. NPJ Precis. Oncol. 6, 3 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Liang, H. C. et al. The NPM1-TYK2 chimeric fusion promotes activation of STAT family signaling, skewing towards Tfh functional subset differentiation and mature T-cell lymphomagenesis. Blood 140, 9281–9282 (2022).

Article 

Google Scholar
 

Crescenzo, R. et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27, 516–532 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Odejide, O. et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 123, 1293–1296 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Nishanth, G. et al. Gain of function in Jak2(V617F)-positive T-cells. Leukemia 31, 1000–1003 (2017).

Article 
CAS 
PubMed 

Google Scholar
 

Bahar, B., Barton, K. & Kini, A. R. The role of the exon 13 G571S JAK2 mutation in myeloproliferative neoplasms. Leuk. Res. Rep. 6, 27–28 (2016).

PubMed 
PubMed Central 

Google Scholar
 

McGirt, L. Y. et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood 126, 508–519 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Schatz, J. H. et al. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia 29, 237–241 (2015).

Article 
CAS 
PubMed 

Google Scholar
 

Bellanger, D. et al. Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 28, 417–419 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Koskela, H. L. et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med. 366, 1905–1913 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Kiel, M. J. et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat. Commun. 6, 8470 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Koo, G. C. et al. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2, 591–597 (2012).

Article 
CAS 
PubMed 

Google Scholar
 

Waldmann, T. A. & Chen, J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis: implications for immunotherapy. Annu. Rev. Immunol. 35, 533–550 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Heim, M. H., Kerr, I. M., Stark, G. R. & Darnell, J. E. Jr. Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267, 1347–1349 (1995).

Article 
CAS 
PubMed 

Google Scholar
 

Kiel, M. J. et al. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 124, 1460–1472 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Kucuk, C. et al. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat. Commun. 6, 6025 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Rajala, H. L. et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 121, 4541–4550 (2013).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Grabstein, K. H. et al. Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science 264, 965–968 (1994).

Article 
CAS 
PubMed 

Google Scholar
 

Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Schrader, A. et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat. Commun. 9, 697 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Herling, M. et al. High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia. Blood 111, 328–337 (2008).

Article 
CAS 
PubMed 

Google Scholar
 

Chen, Y. W. et al. Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma. Blood 125, 1589–1600 (2015).

Article 
CAS 
PubMed 

Google Scholar
 

Kleppe, M. et al. Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma. Haematologica 96, 1723–1727 (2011).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Simoncic, P. D., Lee-Loy, A., Barber, D. L., Tremblay, M. L. & McGlade, C. J. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr. Biol. 12, 446–453 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 186, 683–693 (1997).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J. Clin. Invest. 121, 4758–4774 (2011).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Karaca Atabay, E. et al. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma. Blood 139, 717–731 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wartewig, T. & Ruland, J. PD-1 tumor suppressor signaling in T cell lymphomas. Trends Immunol. 40, 403–414 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Wartewig, T. et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121–125 (2017). This study identified PD1 as a tumour suppressor in T-NHL and showed that it is frequently mutated in human cases.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Park, J. et al. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood 138, 1225–1236 (2021). This study demonstrated that loss of PD1 has prognostic significance in human cutaneous T-NHL.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wartewig, T. et al. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma. Nat. Cancer 4, 1508–1525 (2023). This study identified PD1-dependent tumour-suppressor regulation of metabolic and epigenetic programs in T-NHL.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Ratner, L., Waldmann, T. A., Janakiram, M. & Brammer, J. E. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N. Engl. J. Med. 378, 1947–1948 (2018). This study was the first to report hyperprogression of human T-NHL after pharmacological PD1 checkpoint.

Article 
PubMed 

Google Scholar
 

Rauch, D. A. et al. Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood 134, 1406–1414 (2019).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Gao, Y. et al. Hyperprogression of cutaneous T cell lymphoma after anti-PD-1 treatment. JCI Insight 8, e164793 (2023).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Anand, K. et al. T-cell lymphoma secondary to checkpoint inhibitor therapy. J Immunother. Cancer 8, e000104 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Ungewickell, A. et al. Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nat. Genet. 47, 1056–1060 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).

Article 
CAS 
PubMed 

Google Scholar
 

Coornaert, B. et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nat. Immunol. 9, 263–271 (2008).

Article 
CAS 
PubMed 

Google Scholar
 

Takagi, M. et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J. Allergy Clin. Immunol. 139, 1914–1922 (2017).

Article 
CAS 
PubMed 

Google Scholar
 

Braun, F. C. et al. Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sezary syndrome. Leukemia 25, 1494–1501 (2011).

Article 
CAS 
PubMed 

Google Scholar
 

Ahn, H., Yang, J. M., Jeon, Y. K. & Paik, J. H. Clinicopathologic implications of TNFAIP3/A20 deletions in extranodal NK/T-cell lymphoma. Genes Chromosomes Cancer 57, 231–239 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Chen, C. et al. TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma. Cancer Cell Int. 21, 490 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wang, C. et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126, 1741–1752 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Mao, X. et al. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood 101, 1513–1519 (2003).

Article 
CAS 
PubMed 

Google Scholar
 

Byrd, J. C. et al. A phase I, first-in-human study of ONO-7018 in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. J. Clin. Oncol. https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS708 (2024).

Article 
PubMed 

Google Scholar
 

Nguyen, T. B. et al. Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma. Cancer Res. 80, 1875–1884 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

Kumar, A. et al. Pilot trial of ibrutinib in patients with relapsed or refractory T-cell lymphoma. Blood Adv. 2, 871–876 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03372057 (2025).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03770000 (2022).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03952078 (2019).

US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02567656 (2015).

Iyer, S. P. et al. Final results of phase 1/1b study of tenalisib, dual PI3K δ/γ inhibitor in patients with relapsed/refractory T-cell lymphoma. Blood 134, 2831 (2019).

Article 

Google Scholar
 

Braun, T. et al. Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody. Nat. Med. 31, 1145–1153 (2025).

Article 
CAS 
PubMed 

Google Scholar
 

Perica, K. et al. CD4+ T-cell lymphoma harboring a chimeric antigen receptor integration in TP53. N. Engl. J. Med. 392, 577–583 (2025).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Jain, N. et al. TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 615, 315–322 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Manso, R. et al. Recurrent presence of the PLCG1 S345F mutation in nodal peripheral T-cell lymphomas. Haematologica 100, e25–e27 (2015).

Article 
PubMed 

Google Scholar
 

Hornakova, T. et al. Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor α homodimers. J. Biol. Chem. 284, 6773–6781 (2009).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Malinge, S. et al. Activating mutations in human acute megakaryoblastic leukemia. Blood 112, 4220–4226 (2008).

Article 
CAS 
PubMed 

Google Scholar
 

Lobello, C. et al. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma. Leukemia 35, 1500–1505 (2021).

Article 
CAS 
PubMed 

Google Scholar