WANG Yimeng,ZHANG Chunlei.Progress in Molecular Mechanisms Relating to the Onset of Cutaneous T-cell Lymphoma[J].The Chinese Journal of Dermatovenereology,2019,(05):580-584.[doi:10.13735/j.cjdv.1001-7089.201809002]





Progress in Molecular Mechanisms Relating to the Onset of Cutaneous T-cell Lymphoma
WANG YimengZHANG Chunlei
(Department of Dermatology,Peking University Third Hospital,Beijing 100191,China)
Cutaneous T-cell lymphomaMolecular mechanismSignal pathwayGene
R 739.5
皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma,CTCL)代表了一类由皮肤归巢恶性T淋巴细胞克隆性增生引起的疾病。CTCL发病机制复杂,目前尚不明确。公认的与CTCL发生密切相关的分子机制包括JAK/STAT、MAPK、NOTCH通路的失调,以及一些原癌/抑癌基因的异常以及非编码RNA引起的表观遗传学的变化等。本文对CTCL相关的分子机制的研究进展进行综述。
Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of neoplasms caused by skin-homing malignant T-lymphocytes.Currently, the pathogenesis of CTCL is complex and unclear.It generally accepted that the molecular mechanisms involved in the onset of CTCL include dysregulation of JAK/STAT, MAPK and NOTCH signal pathways, abnormal oncogenes/tumor suppressor genes and epigenetic changes caused by non-coding RNA.In this article, we overview recent progress in molecular mechanisms of CTCL.


[1]Sidiropoulos KG, Martinez-Escala ME, Yelamos O, et al.Primary cutaneous T-cell lymphomas: a review[J].J Clin Pathol, 2015, 68(12):1003-1010.
[2] Li JY, Horwitz S, Moskowitz A, et al.Management of cutaneous T cell lymphoma: new and emerging targets and treatment options[J].Cancer Manag Res, 2012, 4:75-89.
[3] Swerdlow SH, Campo E, Pileri SA, et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms[J].Blood, 2016, 127(20):2375-2390.
[4] Kempf W, Kerl K, Mitteldorf C.Cutaneous CD30-positive T-cell lymphoproliferative disorders-clinical and histopathologic features, differential diagnosis, and treatment[J].Semin Cutan Med Surg, 2018, 37(1):24-29.
[5] Roskoski RJ.Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases[J].Pharmacol Res, 2016, 111:784-803.
[6] Yan Z, Gibson SA, Buckley JA, et al.Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases[J].Clin Immunol, 2018, 189: 4-13.
[7] Chou DH, Vetere A, Choudhary A, et al.Kinase-independent small-molecule inhibition of JAK-STAT signaling[J].J Am Chem Soc, 2015, 137(24):7929-7934.
[8] Cornejo MG, Kharas MG, Werneck MB, et al.Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models[J].Blood, 2009, 113(12):2746-2754.
[9] Kucuk C, Jiang B, Hu X, et al.Activating mutations of STAT5B and STAT3 in lymphomas derived from gammadelta-T or NK cells[J].Nat Commun, 2015, 6:6025.
[10] McGirt LY, Jia P, Baerenwald DA, et al.Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides[J].Blood, 2015, 126(4):508-519.
[11] Koo GC, Tan SY, Tang T, et al.Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma[J].Cancer Discov, 2012, 2(7):591-597.
[12] Yang H, Ma P, Cao Y, et al.ECPIRM, apotential therapeutic agent for cutaneous T-cell lymphoma, inhibits cell proliferation and promotes apoptosis via a JAK/STAT Pathway[J].Anticancer Agents Med Chem, 2018, 18(3):401-411.
[13] Yu L, Li L, Medeiros LJ, et al.NF-kappaB signaling pathway and its potential as a target for therapy in lymphoid neoplasms[J].Blood Rev, 2017, 31(2):77-92.
[14] Park J, Yang J, Wenzel AT, et al.Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E)[J].Blood, 2017, 130(12):1430-1440.
[15] da Silva Almeida AC, Abate F, Khiabanian H, et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome[J].Nat Genet, 2015, 47(12):1465-1470.
[16] Jiang L, Gu ZH, Yan ZX, et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma[J].Nat Genet, 2015, 47(9):1061-1066.
[17] Bridges E, Oon CE Harris A.Notch regulation of tumor angiogenesis[J].Future Oncol, 2011, 7(4):569-588.
[18] Lobry C, Oh P, Mansour MR, et al.Notch signaling: switching an oncogene to a tumor suppressor[J].Blood, 2014, 123(16):2451-2459.
[19] Kamstrup MR, Ralfkiaer E, Skovgaard GL, et al.Potential involvement of Notch1 signalling in the pathogenesis of primary cutaneous CD30-positive lymphoproliferative disorders[J].Br J Dermatol, 2008, 158(4):747-753.
[20] van der Fits L, Qin Y, Out-Luiting JJ, et al.NOTCH1 signaling as a therapeutic target in Sezary syndrome[J].J Invest Dermatol, 2012, 132(12):2810-2817.
[21] Gallardo F, Sandoval J, Diaz-Lagares A, et al.Notch1pathway activation results from the epigenetic abrogation of notch-related microRNAs in mycosis fungoides[J].J Invest Dermatol, 2015, 135(12):3144-3152.
[22] Kamstrup MR, Biskup E, Manfe V, et al.Chemotherapeutic treatment is associated with Notch1 induction in cutaneous T-cell lymphoma[J].Leuk Lymphoma, 2017, 58(1):171-178.
[23] Woollard WJ, Kalaivani NP, Jones CL, et al.Independentloss of methylthioadenosine phosphorylase (MTAP) in primary cutaneous T-Cell Lymphoma[J].J Invest Dermatol, 2016, 136(6):1238-1246.
[24] Poi MJ, Knobloch TJ and Li J.Deletion of RD(INK4/ARF) enhancer: A novel mutation to "inactivate" the INK4-ARF locus[J].DNA Repair (Amst), 2017, 57:50-55.
[25] Salgado R, Servitje O, Gallardo F, et al.Oligonucleotide array-CGH identifies genomic subgroups and prognostic markers for tumor stage mycosis fungoides[J].J Invest Dermatol, 2010, 130(4):1126-1135.
[26] Nicolae-Cristea AR, Benner MF, Zoutman WH, et al.Diagnostic and prognostic significance of CDKN2A/CDKN2B deletions in patients with transformed mycosis fungoides and primary cutaneous CD30-positive lymphoproliferative disease[J].Br J Dermatol, 2015, 172(3):784-788.
[27] Laharanne E, Chevret E, Idrissi Y, et al.CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma[J].Mod Pathol, 2010, 23(4):547-558.
[28] Zhang C, Toulev A, Kamarashev J, et al.Consequences of p16 tumor suppressor gene inactivation in mycosis fungoides and Sezary syndrome and role of the bmi-1 and ras oncogenes in disease progression[J].Hum Pathol, 2007, 38(7):995-1002.
[29] Boosani CS,Agrawal DK.PTEN modulators: a patent review[J].Expert Opin Ther Pat, 2013, 23(5):569-580.
[30] Worby CA,Dixon JE.Pten[J].Annu Rev Biochem, 2014, 83:641-669.
[31] Hollander MC, Blumenthal GM ,Dennis PA.PTEN loss in the continuum of common cancers, rare syndromes and mouse models[J].Nat Rev Cancer, 2011, 11(4):289-301.
[32] Baquero P, Jimenez-Mora E, Santos A, et al.TGFbeta induces epithelial-mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways[J].Mol Carcinog, 2016, 55(11):1639-1654.
[33] Deb TB, Barndt RJ, Zuo AH, et al.PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression[J].Cell Cycle, 2014, 13(6):961-973.
[34] Katona TM, Smoller BR, Webb AL, et al.Expression of PTEN in mycosis fungoides and correlation with loss of heterozygosity[J].Am J Dermatopathol, 2013, 35(5):555-560.
[35] Grzanka D, Gagat M, Izdebska M, et al.Expression of special AT-rich sequence-binding protein 1 is an independent prognostic factor in cutaneous T-cell lymphoma[J].Oncol Rep, 2015, 33(1):250-266.
[36] Fromberg A, Engeland K ,Aigner A.Thespecial AT-rich sequence binding Protein 1 (SATB1) and its role in solid tumors[J].Cancer Lett, 2018, 417:96-111.
[37] Choudhary D, Clement JM, Choudhary S, et al.SATB1 and bladder cancer: Is there a functional link?[J].Urol Oncol, 2018, 36(3):93 e13-93 e21.
[38] Chen H, Takahara M, Oba J, et al.Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanoma[J].J Dermatol Sci, 2011, 64(1):39-44.
[39] Al-Sohaily S, Henderson C, Selinger C, et al.Loss of special AT-rich sequence-binding protein 1 (SATB1) predicts poor survival in patients with colorectal cancer[J].Histopathology, 2014, 65(2):155-163.
[40] Wang Y, Gu X, Zhang G, et al.SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+lymphoproliferative disease by repressing p21[J].Blood, 2014, 123(22):3452-3461.
[41] Lund E, Guttinger S, Calado A, et al.Nuclear export of microRNA precursors[J].Science, 2004, 303(5654):95-98.
[42] Wahid F, Shehzad A, Khan T, et al.MicroRNAs: synthesis, mechanism, function, and recent clinical trials[J].Biochim Biophys Acta, 2010, 1803(11):1231-1243.
[43] Bueno MJ, Malumbres M.MicroRNAs and the cell cycle[J].Biochim Biophys Acta, 2011, 1812(5):592-601.
[44] Martinez-Escala ME, Choi J.Are microRNAs key to developing biomarkers for cutaneous T-cell lymphoma?[J].J Invest Dermatol, 2018, 138(9):1906-1908.
[45] Martinez I, Dimaio D.B-Myb, cancer, senescence, and microRNAs[J].Cancer Res, 2011, 71(16):5370-5373.
[46] Shen X, Wang B, Li K, et al.MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma[J].J Invest Dermatol, 2018, 138(9):2024-2032.
[47] Sandoval J, Diaz-Lagares A, Salgado R, et al.MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma[J].J Invest Dermatol, 2015, 135(4):1128-1137.
[48] Lindahl LM, Besenbacher S, Rittig AH, et al.Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study[J].Blood, 2018, 131(7):759-770.
[49] Tensen CP, Vermeer MH.MicroRNA-155 potentiates tumour development in mycosis fungoides[J].Br J Dermatol, 2017, 177(3):618-620.
[50] Ralfkiaer U, Lindahl LM, Litman T, et al.MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma[J].Anticancer Res, 2014, 34(12):7207-7217.


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 AI Jun,XU Ji xiang,HUANG Juan,et al.Atypical Hydroa Vacciniforme:A Case Report[J].The Chinese Journal of Dermatovenereology,2015,(05):171.[doi:10.13735/j.cjdv.1001-7089.201404039]
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[基金项目]国家自然科学基金面上项目( 81372915)
[作者单位] 北京大学第三医院皮肤科,北京100191
[通讯作者] 张春雷,E-mail: zhangchunleius@163.com
更新日期/Last Update: 2019-04-15