Pathogenesis of Enteropathy-Associated T Cell Lymphoma
Purpose of Review
To provide an update on the pathogenesis of enteropathy-associated T cell lymphoma (EATL) and its relationship with refractory celiac disease (RCD), in light of current knowledge of immune, genetic, and environmental factors that promote neoplastic transformation of intraepithelial lymphocytes (IELs).
EATL frequently evolves from RCD type II (RCD II) but can occur “de novo” in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL.
The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.
KeywordsEATL T cell lymphoma Celiac disease Refractory celiac disease Intestine Genetics
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts 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.
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- 1.CE SSH, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, et al. WHO classification of tumours and haematopoietic and lymphoid tissues. Revised 4th Edition ed. Lyon, France: IARC; 2017.Google Scholar
- 5.Swerdlow SHCE, Harris NL, et al., editors. World Health Organization classification of tumors of haematopoietic and lymphoid tissues. Lyon, France: IARC; 2008.Google Scholar
- 6.• Tack GJ, van Wanrooij RL, Langerak AW, Tjon JM, von Blomberg BM, Heideman DA, et al. Origin and immunophenotype of aberrant IEL in RCDII patients. Mol Immunol. 2012;50(4):262–70. Phenotypic and genotypic (TCR gene rearrangement) analysis of refractory celiac disease type II (RCD II) intraepithelial lymphocytes, which suggested an origin of RCD II from T/NK-cell precursors. PubMedGoogle Scholar
- 7.• Schmitz F, Tjon JM, Lai Y, Thompson A, Kooy-Winkelaar Y, Lemmers RJ, et al. Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II. Gut. 2013;62(4):509–19. Phenotypic and gene expression analysis of innate intraepithelial lymphocytes and RCD II cell lines suggested a novel cell of origin of RCD II. PubMedGoogle Scholar
- 8.• Schmitz F, Tjon JM, van Bergen J, Koning F. Dendritic cells promote expansion and survival of aberrant TCR-negative intraepithelial lymphocyte lines from refractory celiac disease type II patients. Mol Immunol. 2014;58(1):10–6. Identification of selective stimulation of RCD II intraepithelial lymphocytes by dendritic cells in the absence of IL-15. PubMedGoogle Scholar
- 9.• Schmitz F, Kooy-Winkelaar Y, Wiekmeijer AS, Brugman MH, Mearin ML, Mulder C, et al. The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease. Gut. 2016;65(8):1269–78. Comparative phenotypic and transcriptional analysis of RCD II intraepithelial lymphocytes and T cells revealed lack of differentiation potential of RCD II. PubMedGoogle Scholar
- 10.• Ettersperger J, Montcuquet N, Malamut G, Guegan N, Lopez-Lastra S, Gayraud S, et al. Interleukin-15-dependent T-cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease. Immunity. 2016;45(3):610–25. In vivo and in vitro functional characterization of innate lymphocyte development to identify the cell of origin of RCD II and description of frequent JAK I and STAT3 mutations in RCD II. PubMedGoogle Scholar
- 11.• Kooy-Winkelaar YM, Bouwer D, Janssen GM, Thompson A, Brugman MH, Schmitz F, et al. CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes. Proc Natl Acad Sci U S A. 2017;114(6):E980–E9. Evidence that gliadin responsive CD4+ T cells in the lamina propria can communicate with and stimulate the proliferation and survival of innate intraepithelial lymphocytes in RCD II. PubMedPubMedCentralGoogle Scholar
- 12.• Roberti A, Dobay MP, Bisig B, Vallois D, Boechat C, Lanitis E, et al. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Commun. 2016;7:12602. Whole exome sequencing of MEITL (formerly EATL II) revealed frequent inactivating mutations and deletions of SETD2 that were absent in EATL (formerly EATL I), the latter showing frequent JAK1 and STAT3 mutations. PubMedPubMedCentralGoogle Scholar
- 13.• Nicolae A, Xi L, Pham TH, Pham TA, Navarro W, Meeker HG, et al. Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas. Leukemia. 2016;30(11):2245–7. Targeted next-generation sequencing of EATL, MEITL, and PTCL, NOS, identified overlapping spectrum of mutations in these entities. PubMedPubMedCentralGoogle Scholar
- 14.•• Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, et al. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med. 2017;214(5):1371–86. Whole exome sequencing of EATL and MEITL revealed overlapping spectrum of mutations, with both entities showing frequent recurrent mutations in SETD2 and members of the JAK-STAT signaling pathway. In vivo functional analysis of SETD2 loss using a mouse model revealed a role of SETD2 in T cell lineage specification. PubMedPubMedCentralGoogle Scholar
- 17.A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood. 1997;89(11):3909–18.Google Scholar
- 18.• Malamut G, Chandesris O, Verkarre V, Meresse B, Callens C, Macintyre E, et al. Enteropathy associated T cell lymphoma in celiac disease: a large retrospective study. Dig Liver Dis. 2013;45(5):377–84. Retrospective analysis highlighting different clinicopathogentic characteristics of RCD II-derived and de novo EATL. PubMedGoogle Scholar
- 35.Leonard JN, Tucker WF, Fry JS, Coulter CA, Boylston AW, McMinn RM, et al. Increased incidence of malignancy in dermatitis herpetiformis. Br Med J (Clin Res Ed). 1983;286(6358):16–8.Google Scholar
- 45.Jewell DP. Ulcerative enteritis. Br Med J (Clin Res Ed). 1983;287(6407):1740–1.Google Scholar
- 50.Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group Lancet. 2000;356(9225):203–8.Google Scholar
- 63.Verbeek WH, Goerres MS, von Blomberg BM, Oudejans JJ, Scholten PE, Hadithi M, et al. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease. Clin Immunol. 2008;126(1):48–56.PubMedGoogle Scholar
- 74.Hrdlickova B, Mulder CJ, Malamut G, Meresse B, Platteel M, Kamatani Y, et al. A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease. Eur J Gastroenterol Hepatol. 2018. https://doi.org/10.1097/MEG.0000000000001168.
- 77.Jarry A, Cerf-Bensussan N, Brousse N, Selz F, Guy-Grand D. Subsets of CD3+ (T cell receptor alpha/beta or gamma/delta) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. 1990;20(5):1097–103.PubMedGoogle Scholar
- 83.Spencer J, Cerf-Bensussan N, Jarry A, Brousse N, Guy-Grand D, Krajewski AS, et al. Enteropathy-associated T cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal antibody (HML-1) that defines a membrane molecule on human mucosal lymphocytes. Am J Pathol. 1988;132(1):1–5.PubMedPubMedCentralGoogle Scholar
- 84.Lambolez F, Mayans S, Cheroutre H. Lymphocytes: intraepithelial. eLS. Hoboken: John Wiley & Sons, Ltd; 2001.Google Scholar
- 86.Jaffe ESAD, Campo E, Harris NL, Quintanilla-Fend L. Hematopathology. 2nd Edition ed. Philadelphia. USA: Elsevier; 2016.Google Scholar
- 87.Attygalle AD, Cabecadas J, Gaulard P, Jaffe ES, de Jong D, Ko YH, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward—report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology. 2014;64(2):171–99.PubMedGoogle Scholar
- 89.van Wanrooij RL, de Jong D, Langerak AW, Ylstra B, van Essen HF, Heideman DA, et al. Novel variant of EATL evolving from mucosal γδ-T-cells in a patient with type I RCD. BMJ Open Gastroenterol. 2015;2(1):e000026. https://doi.org/10.1136/bmjgast-2014-000026.
- 99.Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest. 2010;120(6):2131–43.PubMedPubMedCentralGoogle Scholar
- 104.• Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132(5):1902–11. Array-based genomic analysis and HLA genotyping showed differences and similarities of genomic changes in EATL (formerly EATL I) and MEITL (formerly EATL II). PubMedGoogle Scholar