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Genetics of Cutaneous T Cell Lymphoma: From Bench to Bedside

  • William E. Damsky
  • Jaehyuk Choi
Skin Cancer (BY Kwong, Section Editor)
First Online:
Part of the following topical collections:
  1. Topical Collection on Skin Cancer

Opinion statement

Cutaneous T cell lymphomas (CTCLs) are non-Hodgkin lymphomas of skin homing T cells. Although early-stage disease may be limited to the skin, tumor cells in later stage disease can populate the blood, the lymph nodes, and the visceral organs. Unfortunately, there are few molecular biomarkers to guide diagnosis, staging, or treatment of CTCL. Diagnosis of CTCL can be challenging and requires the synthesis of clinical findings, histopathology, and T cell clonality studies; however, none of these tests are entirely sensitive or specific for CTCL. Treatment of CTCL is often empiric and is not typically based on specific molecular alterations, as is common in other cancers. In part, limitations in diagnosis and treatment selection reflect the limited insight into the genetic basis of CTCL. Recent next-generation sequencing has revolutionized our understanding of the mutational landscape in this disease. These analyses have uncovered ultraviolet radiation and recombination activating gene (RAG) endonucleases as important mutagens. Furthermore, these studies have revealed potentially targetable oncogenic mutations in the T cell receptor complex, NF-κB, and JAK-STAT signaling pathways. Collectively, these somatic mutations drive lymphomagenesis via cancer-promoting changes in proliferation, apoptosis, and T cell effector function. We expect that these genetic findings will launch a new era of precision medicine in CTCL.

Keywords

Cutaneous T cell lymphoma CTCL Mycosis fungoides Next-generation sequencing JAK-STAT NF-κB Bortezomib Tofacitinib Ruxolitinib 
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Notes

Compliance with Ethical Standards

Conflict of Interest

William E. Damsky and Jaehyuk Choi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. The New England journal of medicine. 2004;350(19):1978–88. doi: 10.1056/NEJMra032810.CrossRefPubMedGoogle Scholar
  2. 2.••
    Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, et al. Genomic landscape of cutaneous T cell lymphoma. Nature genetics. 2015;47(9):1011–9. doi: 10.1038/ng.3356. Exome analysis of 40 late stage mycosis fungoides specimens identifying recurrent pathogenic mutations in 17 genes. These mutations include ZEB1, FAS, NFKB2, and STAT5B, among others. Also identifies that the majority of pathogenic mutations in MF are SCNVs (specifically focal deletions) and that a there is a high prevalence of UV signature mutations in MF.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.••
    Ungewickell A, Bhaduri A, Rios E, Reuter J, Lee CS, Mah A, et al. Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nature genetics. 2015;47(9):1056–60. doi: 10.1038/ng.3370. Exome analysis of 11 MF/SS specimens that identified and characterized the effect of recurrent mutations in tumor necrosis factor receptor TNFR2 (TNFRSF1B gene) as a mechanism by which NF-κB signaling is activated in CTCL. Also show that TNFRS1B mutant CTCLs are sensitive to NF-κB blockade with the proteasome inhibitor bortezomib.CrossRefPubMedGoogle Scholar
  4. 4.••
    da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, et al. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nature genetics. 2015;47(12):1465–70. doi: 10.1038/ng.3442. Exome analysis of 25 SS, 8 MF, and 9 other CTCL variants that identified recurrent mutations in NF-κB, JAK-STAT, and T cell receptor pathways. Specifically identifies JAK3 and STAT3 mutations in CTCL and show that these mutations are targetable using JAK-STAT pathway inhibitors tofacitinib and ruxolitinib.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.••
    Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nature genetics. 2015;47(12):1426–34. doi: 10.1038/ng.3444. Exome analysis of 37 SS samples identified recurrently mutated components of T cell signaling such as CARD11 and PDCD1 (PD-1) which result in constitutive TCR pathway activation. Also identified recurrent mutations involved in TH2 functional polarization (ZEB1) and skin homing (CCR4).CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.•
    McGirt LY, Jia P, Baerenwald DA, Duszynski RJ, Dahlman KB, Zic JA, et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood. 2015;126(4):508–19. doi: 10.1182/blood-2014-11-611194. Exome analysis of 5 tumor stage MF samples identified JAK3 mutations. Show that JAK3 mutant cells are sensitive to JAK-STAT pathway inhibition.CrossRefPubMedGoogle Scholar
  7. 7.
    Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al. Defining early mycosis fungoides. Journal of the American Academy of Dermatology. 2005;53(6):1053–63. doi: 10.1016/j.jaad.2005.08.057.CrossRefPubMedGoogle Scholar
  8. 8.
    Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768–85. doi: 10.1182/blood-2004-09-3502.CrossRefPubMedGoogle Scholar
  9. 9.
    Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/sezary syndrome: validation of the revised international society for Cutaneous Lymphomas/European Organisation for research and treatment of cancer staging proposal. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(31):4730–9. doi: 10.1200/JCO.2009.27.7665.CrossRefGoogle Scholar
  10. 10.
    Watanabe R, Gehad A, Yang C, Scott LL, Teague JE, Schlapbach C, et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Science translational medicine. 2015;7(279):279ra39. doi: 10.1126/scitranslmed.3010302.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Clark RA, Watanabe R, Teague JE, Schlapbach C, Tawa MC, Adams N, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Science translational medicine. 2012;4(117):117ra7. doi: 10.1126/scitranslmed.3003008.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010;116(5):767–71. doi: 10.1182/blood-2009-11-251926.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, Hladik F, et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. The Journal of experimental medicine. 2007;204(3):595–603. doi: 10.1084/jem.20061792.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhu J, Peng T, Johnston C, Phasouk K, Kask AS, Klock A, et al. Immune surveillance by CD8alphaalpha + skin-resident T cells in human herpes virus infection. Nature. 2013;497(7450):494–7. doi: 10.1038/nature12110.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Guitart J, Kennedy J, Ronan S, Chmiel JS, Hsiegh YC, Variakojis D. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting. Journal of cutaneous pathology. 2001;28(4):174–83.CrossRefPubMedGoogle Scholar
  16. 16.
    Smoller BR, Bishop K, Glusac E, Kim YH, Hendrickson M. Reassessment of histologic parameters in the diagnosis of mycosis fungoides. The American journal of surgical pathology. 1995;19(12):1423–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Criteria for histologic diagnosis. The American Journal of dermatopathology. 1979;1(1):5–26.CrossRefPubMedGoogle Scholar
  18. 18.
    van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia. 2003;17(12):2257–317. doi: 10.1038/sj.leu.2403202.CrossRefPubMedGoogle Scholar
  19. 19.
    Ponti R, Fierro MT, Quaglino P, Lisa B, Paola F, Michela O, et al. TCRgamma-chain gene rearrangement by PCR-based GeneScan: diagnostic accuracy improvement and clonal heterogeneity analysis in multiple cutaneous T-cell lymphoma samples. The Journal of investigative dermatology. 2008;128(4):1030–8. doi: 10.1038/sj.jid.5701109.CrossRefPubMedGoogle Scholar
  20. 20.
    Weed J, Girardi M. The difficult--and often delayed--diagnosis of CTCL. Science translational medicine. 2015;7(308):308fs41. doi: 10.1126/scitranslmed.aad2518.CrossRefPubMedGoogle Scholar
  21. 21.
    Schiller PI, Flaig MJ, Puchta U, Kind P, Sander CA. Detection of clonal T cells in lichen planus. Archives of dermatological research. 2000;292(11):568–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Dereure O, Levi E, Kadin ME. T-Cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. Archives of dermatology. 2000;136(12):1483–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Lukowsky A, Muche JM, Sterry W, Audring H. Detection of expanded T cell clones in skin biopsy samples of patients with lichen sclerosus et atrophicus by T cell receptor-gamma polymerase chain reaction assays. The Journal of investigative dermatology. 2000;115(2):254–9. doi: 10.1046/j.1523-1747.2000.00040.x.CrossRefPubMedGoogle Scholar
  24. 24.
    Duvic M, Vu J. Update on the treatment of cutaneous T-cell lymphoma (CTCL): focus on vorinostat. Biologics. 2007;1(4):377–92.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Dereure O, Levi E, Vonderheid EC, Kadin ME. Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin. The Journal of investigative dermatology. 2002;118(6):949–56. doi: 10.1046/j.1523-1747.2002.01794.x.CrossRefPubMedGoogle Scholar
  26. 26.
    van Doorn R, Dijkman R, Vermeer MH, Starink TM, Willemze R, Tensen CP. A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma. Cancer research. 2002;62(19):5389–92.PubMedGoogle Scholar
  27. 27.
    Contassot E, Kerl K, Roques S, Shane R, Gaide O, Dupuis M, et al. Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression. Blood. 2008;111(9):4780–7. doi: 10.1182/blood-2007-08-109074.CrossRefPubMedGoogle Scholar
  28. 28.
    Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. The Journal of clinical investigation. 2005;115(4):798–812. doi: 10.1172/JCI24826.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Heald P, Yan SL, Edelson R. Profound deficiency in normal circulating T cells in erythrodermic cutaneous T-cell lymphoma. Archives of dermatology. 1994;130(2):198–203.CrossRefPubMedGoogle Scholar
  30. 30.
    Levy S, Tempe JL, Caussade P, Aleksijevic A, Grosshans E, Mayer S, et al. Stage-related decrease in natural killer cell activity in untreated patients with mycosis fungoides. Cancer Immunol Immunother. 1984;18(2):138–40.CrossRefPubMedGoogle Scholar
  31. 31.
    Laroche L, Kaiserlian D. Decreased natural-killer-cell activity in cutaneous T-cell lymphomas. The New England journal of medicine. 1983;308(2):101–2. doi: 10.1056/NEJM198301133080213.PubMedGoogle Scholar
  32. 32.
    Saed G, Fivenson DP, Naidu Y, Nickoloff BJ. Mycosis fungoides exhibits a Th1-type cell-mediated cytokine profile whereas Sezary syndrome expresses a Th2-type profile. The Journal of investigative dermatology. 1994;103(1):29–33.CrossRefPubMedGoogle Scholar
  33. 33.
    Bagot M, Nikolova M, Schirm-Chabanette F, Wechsler J, Boumsell L, Bensussan A. Crosstalk between tumor T lymphocytes and reactive T lymphocytes in cutaneous T cell lymphomas. Annals of the New York Academy of Sciences. 2001;941:31–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang Q, Wang HY, Wei F, Liu X, Paterson JC, Roy D, et al. Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner. Journal of immunology. 2014;192(6):2913–9. doi: 10.4049/jimmunol.1302951.CrossRefGoogle Scholar
  35. 35.
    Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Sezary syndrome. JAMA. 1992;267(10):1354–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Goh G, Walradt T, Markarov V, Blom A, Riaz N, Doumani R, et al. Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell carcinomas with implications for immunotherapy. Oncotarget. 2015. doi: 10.18632/oncotarget.6494.Google Scholar
  37. 37.
    Cancer Genome Atlas N. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96. doi: 10.1016/j.cell.2015.05.044.CrossRefGoogle Scholar
  38. 38.
    Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi: 10.1038/nature11412.CrossRefGoogle Scholar
  39. 39.
    Natarajan VT, Ganju P, Ramkumar A, Grover R, Gokhale RS. Multifaceted pathways protect human skin from UV radiation. Nat Chem Biol. 2014;10(7):542–51. doi: 10.1038/nchembio.1548.CrossRefPubMedGoogle Scholar
  40. 40.
    Gaide O, Emerson RO, Jiang X, Gulati N, Nizza S, Desmarais C, et al. Common clonal origin of central and resident memory T cells following skin immunization. Nature medicine. 2015;21(6):647–53. doi: 10.1038/nm.3860.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Roth DB. V(D)J recombination: mechanism, errors, and fidelity. Microbiol Spectr. 2014;2(6). doi:  10.1128/microbiolspec.MDNA3-0041-2014
  42. 42.
    Marculescu R, Le T, Simon P, Jaeger U, Nadel B. V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. The Journal of experimental medicine. 2002;195(1):85–98.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mendes RD, Sarmento LM, Cante-Barrett K, Zuurbier L, Buijs-Gladdines JG, Povoa V, et al. PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood. 2014;124(4):567–78. doi: 10.1182/blood-2014-03-562751.CrossRefPubMedGoogle Scholar
  44. 44.
    Teng G, Schatz DG. Regulation and Evolution of the RAG Recombinase. Adv Immunol. 2015;128:1–39. doi: 10.1016/bs.ai.2015.07.002.CrossRefPubMedGoogle Scholar
  45. 45.
    Leibowitz ML, Zhang CZ, Pellman D. Chromothripsis: a new mechanism for rapid karyotype evolution. Annual review of genetics. 2015;49:183–211. doi: 10.1146/annurev-genet-120213-092228.CrossRefPubMedGoogle Scholar
  46. 46.
    Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nature genetics. 2013;45(10):1134–40. doi: 10.1038/ng.2760.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Liehr T, Othman MA, Rittscher K, Alhourani E. The current state of molecular cytogenetics in cancer diagnosis. Expert review of molecular diagnostics. 2015;15(4):517–26. doi: 10.1586/14737159.2015.1013032.CrossRefPubMedGoogle Scholar
  48. 48.
    Gerami P, Scolyer RA, Xu X, Elder DE, Abraham RM, Fullen D, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. The American journal of surgical pathology. 2013;37(5):676–84. doi: 10.1097/PAS.0b013e3182753de6.CrossRefPubMedGoogle Scholar
  49. 49.
    Shahbain H, Cooper C, Gerami P. Molecular diagnostics for ambiguous melanocytic tumors. Seminars in cutaneous medicine and surgery. 2012;31(4):274–8. doi: 10.1016/j.sder.2012.09.001.CrossRefPubMedGoogle Scholar
  50. 50.
    Gammon B, Gerami P. Fluorescence in situ hybridization for ambiguous melanocytic tumors. Histology and histopathology. 2012;27(12):1539–42.PubMedGoogle Scholar
  51. 51.
    Gerami P, Li G, Pouryazdanparast P, Blondin B, Beilfuss B, Slenk C, et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms. The American journal of surgical pathology. 2012;36(6):808–17. doi: 10.1097/PAS.0b013e31824b1efd.CrossRefPubMedGoogle Scholar
  52. 52.
    Romo-Tena J, Gomez-Martin D, Alcocer-Varela J. CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun Rev. 2013;12(12):1171–6. doi: 10.1016/j.autrev.2013.07.002.CrossRefPubMedGoogle Scholar
  53. 53.
    Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. The Journal of experimental medicine. 1992;176(6):1595–604.CrossRefPubMedGoogle Scholar
  54. 54.
    Vaque JP, Gomez-Lopez G, Monsalvez V, Varela I, Martinez N, Perez C, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood. 2014;123(13):2034–43. doi: 10.1182/blood-2013-05-504308.CrossRefPubMedGoogle Scholar
  55. 55.
    Sekulic A, Liang WS, Tembe W, Izatt T, Kruglyak S, Kiefer JA, et al. Personalized treatment of Sezary syndrome by targeting a novel CTLA4:CD28 fusion. Molecular genetics & genomic medicine. 2015;3(2):130–6. doi: 10.1002/mgg3.121.CrossRefGoogle Scholar
  56. 56.
    Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89(4):587–96.CrossRefPubMedGoogle Scholar
  57. 57.
    Cleere R, Long A, Kelleher D, O’Neill LA. Autocrine regulation of the transcription factor NF kappa B by TNF alpha in the human T cell lymphoma line Hut 78. Biochemical Society transactions. 1995;23(1):113S.CrossRefPubMedGoogle Scholar
  58. 58.
    O’Connell MA, Cleere R, Long A, O’Neill LA, Kelleher D. Cellular proliferation and activation of NF kappa B are induced by autocrine production of tumor necrosis factor alpha in the human T lymphoma line HuT 78. The Journal of biological chemistry. 1995;270(13):7399–404.CrossRefPubMedGoogle Scholar
  59. 59.
    Giri DK, Aggarwal BB. Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates. The Journal of biological chemistry. 1998;273(22):14008–14.CrossRefPubMedGoogle Scholar
  60. 60.
    Izban KF, Ergin M, Qin JZ, Martinez RL, Pooley RJ, Saeed S, et al. Constitutive expression of NF-kappa B is a characteristic feature of mycosis fungoides: implications for apoptosis resistance and pathogenesis. Human pathology. 2000;31(12):1482–90.CrossRefPubMedGoogle Scholar
  61. 61.
    Sors A, Jean-Louis F, Pellet C, Laroche L, Dubertret L, Courtois G, et al. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood. 2006;107(6):2354–63. doi: 10.1182/blood-2005-06-2536.CrossRefPubMedGoogle Scholar
  62. 62.
    Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends in immunology. 2004;25(6):280–8. doi: 10.1016/j.it.2004.03.008.CrossRefPubMedGoogle Scholar
  63. 63.
    Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, et al. Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity. 2005;23(6):561–74. doi: 10.1016/j.immuni.2005.09.014.CrossRefPubMedGoogle Scholar
  64. 64.
    Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319(5870):1676–9. doi: 10.1126/science.1153629.CrossRefPubMedGoogle Scholar
  65. 65.
    Migliazza A, Lombardi L, Rocchi M, Trecca D, Chang CC, Antonacci R, et al. Heterogeneous chromosomal aberrations generate 3′ truncations of the NFKB2/lyt-10 gene in lymphoid malignancies. Blood. 1994;84(11):3850–60.PubMedGoogle Scholar
  66. 66.
    Zhang J, Chang CC, Lombardi L, Dalla-Favera R. Rearranged NFKB2 gene in the HUT78 T-lymphoma cell line codes for a constitutively nuclear factor lacking transcriptional repressor functions. Oncogene. 1994;9(7):1931–7.PubMedGoogle Scholar
  67. 67.
    Zhou J, Ching YQ, Chng WJ. Aberrant nuclear factor-kappa B activity in acute myeloid leukemia: from molecular pathogenesis to therapeutic target. Oncotarget. 2015;6(8):5490–500. doi: 10.18632/oncotarget.3545.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Legarda-Addison D, Ting AT. Negative regulation of TCR signaling by NF-kappaB2/p100. Journal of immunology. 2007;178(12):7767–78.CrossRefGoogle Scholar
  69. 69.
    Chang TP, Poltoratsky V, Vancurova I. Bortezomib inhibits expression of TGF-beta1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells. Journal of immunology. 2015;194(6):2942–53. doi: 10.4049/jimmunol.1402610.CrossRefGoogle Scholar
  70. 70.
    Zinzani PL, Musuraca G, Tani M, Stefoni V, Marchi E, Fina M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(27):4293–7. doi: 10.1200/JCO.2007.11.4207.CrossRefGoogle Scholar
  71. 71.
    Heider U, Rademacher J, Lamottke B, Mieth M, Moebs M, von Metzler I, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma. European journal of haematology. 2009;82(6):440–9. doi: 10.1111/j.1600-0609.2009.01239.x.CrossRefPubMedGoogle Scholar
  72. 72.
    Juvekar A, Manna S, Ramaswami S, Chang TP, Vu HY, Ghosh CC, et al. Bortezomib induces nuclear translocation of IkappaBalpha resulting in gene-specific suppression of NF-kappaB--dependent transcription and induction of apoptosis in CTCL. Molecular cancer research : MCR. 2011;9(2):183–94. doi: 10.1158/1541-7786.MCR-10-0368.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Eriksen KW, Kaltoft K, Mikkelsen G, Nielsen M, Zhang Q, Geisler C, et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia. 2001;15(5):787–93.CrossRefPubMedGoogle Scholar
  74. 74.
    Fantin VR, Loboda A, Paweletz CP, Hendrickson RC, Pierce JW, Roth JA, et al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Cancer research. 2008;68(10):3785–94. doi: 10.1158/0008-5472.CAN-07-6091.CrossRefPubMedGoogle Scholar
  75. 75.
    Netchiporouk E, Litvinov IV, Moreau L, Gilbert M, Sasseville D, Duvic M. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression. Cell cycle. 2014;13(21):3331–5. doi: 10.4161/15384101.2014.965061.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell cycle. 2013;12(12):1939–47. doi: 10.4161/cc.24987.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Perez C, Gonzalez-Rincon J, Onaindia A, Almaraz C, Garcia-Diaz N, Pisonero H, et al. Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma. Haematologica. 2015;100(11):e450–3. doi: 10.3324/haematol.2015.132837.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Bergmann AK, Schneppenheim S, Seifert M, Betts MJ, Haake A, Lopez C, et al. Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia. Genes, chromosomes & cancer. 2014;53(4):309–16. doi: 10.1002/gcc.22141.CrossRefGoogle Scholar
  79. 79.
    Hornakova T, Springuel L, Devreux J, Dusa A, Constantinescu SN, Knoops L, et al. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica. 2011;96(6):845–53. doi: 10.3324/haematol.2010.036350.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmaki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. The New England journal of medicine. 2012;366(20):1905–13. doi: 10.1056/NEJMoa1114885.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Haddad BR, Gu L, Mirtti T, Dagvadorj A, Vogiatzi P, Hoang DT, et al. STAT5A/B gene locus undergoes amplification during human prostate cancer progression. The American journal of pathology. 2013;182(6):2264–75. doi: 10.1016/j.ajpath.2013.02.044.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Scott LJ. Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73(8):857–74. doi: 10.1007/s40265-013-0065-8.CrossRefPubMedGoogle Scholar
  83. 83.
    McKeage K. Ruxolitinib: a review in polycythaemia vera. Drugs. 2015;75(15):1773–81. doi: 10.1007/s40265-015-0470-2.CrossRefPubMedGoogle Scholar
  84. 84.
    Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(8):2051–9. doi: 10.1158/1078-0432.CCR-13-0279.CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of DermatologyYale University School of MedicineNew HavenUSA
  2. 2.Department of Dermatology and Department of Biochemistry and Molecular GeneticsNorthwestern University Feinberg School of Medicine, Robert H Lurie Medical Research CenterChicagoUSA

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