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Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy

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Abstract

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1’s brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.

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Abbreviations

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

AITL:

Angioimmunoblastic T-cell lymphoma

ALK:

Anaplastic lymphoma kinase

ALPS:

Autoimmune lymphoproliferative syndrome

AML:

Acute myeloid leukemia

BV-CHP:

Brentuximab vedotin + cyclophosphamide therapy

BV-ESHAP:

Brentuximab vedotin + etoposide, methylprednisolone, cytosine arabinose, cisplatin therapy

CHIP:

Clonal hematopoiesis of indeterminate potential

CHOP:

Cyclophosphamide + hydroxydaunorubicin + oncovin + prednisone therapy

CMA:

Chromosomal microarray

cTfh:

Circulating follicular helper T-cells

DCs:

Dendritic cells

DHAP:

Cisplatin, cytosine arabinoside and dexamethasone therapy

DLBCL:

Diffuse large B-cell lymphoma

DNMT3A:

DNA methyltransferase 3 Alpha

DNT:

Double-negative T-cells

EBER:

Epstein-Barr virus-encoded small RNAs

FAS:

Fas cell surface death receptor

FASL:

Fas ligand

FDG:

18F-Fluorodeoxiglucosa

gnomAD:

Genome Aggregation Database

HDL:

High-density lipoprotein

HSCT:

Hematopoietic stem cell transplant

IEI:

Inborn error of immunity

IgG:

Immunoglobulin G

IL-10:

Interleukin 10

KMT2D:

Lysine methyltransferase 2D

LOF:

Loss of function

NGS:

Next-generation sequencing

NLPHL:

Nodular lymphocyte predominant Hodgkin lymphoma

PET-CT:

Positron emission tomography-computed tomography

SD:

Standard deviation

sFASL:

Soluble Fas ligand

STAT3:

Signal transducer and activator of transcription 3

TEMRA:

Terminally differentiated effector memory T-cells re-expressing CD45RA

TET2:

Ten-eleven translocation-2

Tregs:

Regulatory T-cells

VAF:

Variant allele frequency

VOUS:

Variant of uncertain significance

References

  1. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middelton LA, Lin AY, et al. Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell [Internet]. 1995 Jun 16 [cited 2020 Sep 22];81(6):935–46. Available from: https://pubmed.ncbi.nlm.nih.gov/7540117/.

  2. Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IAG, Debatin KM, Fischer A, et al. Mutations in fas associated with human lymphoproliferative syndrome and autoimmunity. Science (80- ) [Internet]. 1995 [cited 2020 Sep 22];268(5215):1347–9. Available from: https://pubmed.ncbi.nlm.nih.gov/7539157/.

  3. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. In: Blood [Internet]. Blood; 2010 [cited 2020 Sep 22]. Available from: https://pubmed.ncbi.nlm.nih.gov/20538792/.

  4. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol [Internet]. 2020 Jan 1 [cited 2020 Sep 22];40(1):24–64. Available from: https://doi.org/10.1007/s10875-019-00737-x.

  5. Casamayor-Polo L, López-Nevado M, Paz-Artal E, Anel A, Rieux-Laucat F, Allende LM. Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS) [Internet]. Critical Reviews in Clinical Laboratory Sciences. Taylor and Francis Ltd.; 2020 [cited 2021 Jan 4]. Available from: https://pubmed.ncbi.nlm.nih.gov/33356695/.

  6. López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, et al. Primary immune regulatory disorders with an autoimmune lymphoproliferative syndrome-like phenotype: immunologic evaluation, early diagnosis and management. Front Immunol [Internet]. 2021 Aug 10 [cited 2021 Dec 9];12. Available from: https://pubmed.ncbi.nlm.nih.gov/34447369/.

  7. Hauck F, Voss R, Urban C, Seidel MG. Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders. J Allergy Clin Immunol [Internet]. 2018 Jan 1 [cited 2022 Jan 14];141(1):59–68.e4. Available from: https://pubmed.ncbi.nlm.nih.gov/28669558/.

  8. StremenovaSpegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al. Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood. 2020;136(9):1055–66.

    Article  Google Scholar 

  9. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell [Internet]. 2011 [cited 2021 Dec 15];20(1):11–24. Available from: https://pubmed.ncbi.nlm.nih.gov/21723200/.

  10. Tsiouplis NJ, Bailey DW, Chiou LF, Wissink FJ, Tsagaratou A. TET-mediated epigenetic regulation in immune cell development and disease. Front cell Dev Biol [Internet]. 2021 Jan 15 [cited 2021 Dec 15];8. Available from: https://pubmed.ncbi.nlm.nih.gov/33520997/.

  11. Cong B, Zhang Q, Cao X. The function and regulation of TET2 in innate immunity and inflammation. Protein Cell [Internet]. 2021 Mar 1 [cited 2021 Dec 15];12(3):165–73. Available from: https://pubmed.ncbi.nlm.nih.gov/33085059/.

  12. Jiang S. Tet2 at the interface between cancer and immunity. Commun Biol [Internet]. 2020 Dec 1 [cited 2021 Dec 15];3(1). Available from: https://pubmed.ncbi.nlm.nih.gov/33184433/.

  13. Delhommeau F, Dupont S, Valle V Della, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med [Internet]. 2009 May 28 [cited 2021 Dec 15];360(22):2289–301. Available from: https://pubmed.ncbi.nlm.nih.gov/19474426/.

  14. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature [Internet]. 2010 Dec 9 [cited 2021 Dec 15];468(7325):839–43. Available from: https://pubmed.ncbi.nlm.nih.gov/21057493/.

  15. Asmar F, Punj V, Christensen J, Pedersen MT, Pedersen A, Nielsen AB, et al. Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica [Internet]. 2013 Dec 1 [cited 2021 Dec 15];98(12):1912–20. Available from: https://pubmed.ncbi.nlm.nih.gov/23831920/.

  16. Couronné L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med [Internet]. 2012 Jan 5 [cited 2021 Dec 15];366(1):95–6. Available from: https://pubmed.ncbi.nlm.nih.gov/22216861/.

  17. Wu X, Deng J, Zhang N, Liu X, Zheng X, Yan T, et al. Pedigree investigation, clinical characteristics, and prognosis analysis of haematological disease patients with germline TET2 mutation. BMC Cancer [Internet]. 2022 Dec 1 [cited 2022 May 10];22(1). Available from: https://pubmed.ncbi.nlm.nih.gov/35279121/.

  18. Kaasinen E, Kuismin O, Rajamäki K, Ristolainen H, Aavikko M, Kondelin J, et al. Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat Commun [Internet]. 2019 Dec 1 [cited 2021 Dec 15];10(1). Available from: https://pubmed.ncbi.nlm.nih.gov/30890702/.

  19. Duployez N, Goursaud L, Fenwarth L, Bories C, Marceau-Renaut A, Boyer T, et al. Familial myeloid malignancies with germline TET2 mutation. Leukemia [Internet]. 2020 May 1 [cited 2021 Dec 15];34(5):1450–3. Available from: https://pubmed.ncbi.nlm.nih.gov/31827242/.

  20. Gao LM, Zhao S, Zhang WY, Wang M, Li HF, Lizaso A, et al. Somatic mutations in KMT2D and TET2 associated with worse prognosis in Epstein-Barr virus-associated T or natural killer-cell lymphoproliferative disorders. Cancer Biol Ther [Internet]. 2019 Oct 3 [cited 2021 Dec 16];20(10):1319–27. Available from: https://pubmed.ncbi.nlm.nih.gov/31311407/.

  21. Raess PW, Cascio MJ, Fan G, Press R, Druker BJ, Brewer D, et al. Concurrent STAT3, DNMT3A, and TET2 mutations in T-LGL leukemia with molecularly distinct clonal hematopoiesis of indeterminate potential. Am J Hematol [Internet]. 2017 Jan 1 [cited 2021 Dec 16];92(1):E6–8. Available from: https://pubmed.ncbi.nlm.nih.gov/27761930/.

  22. Nair VS, Song MH, Ko M, Oh KI. DNA demethylation of the Foxp3 enhancer is maintained through modulation of ten-eleven-translocation and DNA methyltransferases. Mol Cells [Internet]. 2016 Dec 1 [cited 2021 Dec 29];39(12):888. Available from: https://pubmed.ncbi.nlm.nih.gov/27989104/.

  23. Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet [Internet]. 2014 [cited 2022 Jan 14];46(2):171–5. Available from: https://pubmed.ncbi.nlm.nih.gov/24413737/.

  24. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics [Internet]. 2019 [cited 2020 Dec 17];35(11):1978–80. Available from: https://pubmed.ncbi.nlm.nih.gov/30376034/.

  25. Hanemaaijer NM, Sikkema-Raddatz B, Van Der Vries G, Dijkhuizen T, Hordijk R, Van Essen AJ, et al. Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics. Eur J Hum Genet [Internet]. 2012 Feb [cited 2021 Dec 20];20(2):161–5. Available from: https://pubmed.ncbi.nlm.nih.gov/21934709/.

  26. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med [Internet]. 2020 Feb 1 [cited 2021 Dec 20];22(2):245–57. Available from: https://pubmed.ncbi.nlm.nih.gov/31690835/.

  27. Kwok PY. Methods for genotyping single nucleotide polymorphisms. Annu Rev Genomics Hum Genet [Internet]. 2001 [cited 2022 Feb 12];2:235–58. Available from: https://pubmed.ncbi.nlm.nih.gov/11701650/.

  28. Sriram S, Joshi AY, Rodriguez V, Kumar S. Autoimmune lymphoproliferative syndrome: a rare cause of disappearing HDL syndrome. Case Reports Immunol. 2016;2016:1–4.

    Article  Google Scholar 

  29. Yamazaki J, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Shen L, et al. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics [Internet]. 2012 [cited 2022 Jan 19];7(2):201–7. Available from: https://pubmed.ncbi.nlm.nih.gov/22395470/.

  30. Koskela HLM, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med [Internet]. 2012 May 17 [cited 2021 Dec 16];366(20):1905–13. Available from: https://pubmed.ncbi.nlm.nih.gov/22591296/.

  31. Jerez A, Clemente MJ, Makishima H, Koskela H, LeBlanc F, Ng KP, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood [Internet]. 2012 Oct 11 [cited 2021 Dec 20];120(15):3048–57. Available from: https://pubmed.ncbi.nlm.nih.gov/22859607/.

  32. Fasan A, Kern W, Grossmann V, Haferlach C, Haferlach T, Schnittger S. STAT3 mutations are highly specific for large granular lymphocytic leukemia. Leukemia [Internet]. 2013 Jul [cited 2022 Jan 19];27(7):1598–600. Available from: https://pubmed.ncbi.nlm.nih.gov/23207521/.

  33. Ohgami RS, Ma L, Merker JD, Martinez B, Zehnder JL, Arber DA. STAT3 mutations are frequent in CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia. Leukemia [Internet]. 2013 Nov [cited 2022 Jan 19];27(11):2244–7. Available from: https://pubmed.ncbi.nlm.nih.gov/23563237/.

  34. Lacy SE, Barrans SL, Beer PA, Painter D, Smith AG, Roman E, et al. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report. Blood [Internet]. 2020 May 14 [cited 2022 Jan 19];135(20):1759–71. Available from: https://pubmed.ncbi.nlm.nih.gov/32187361/.

  35. Viguié F, Aboura A, Bouscary D, Ramond S, Delmer A, Tachdjian G, et al. Common 4q24 deletion in four cases of hematopoietic malignancy: early stem cell involvement? Leukemia [Internet]. 2005 [cited 2022 Jan 19];19(8):1411–5. Available from: https://pubmed.ncbi.nlm.nih.gov/15920487/.

  36. Jankowska AM, Szpurka H, Tiu R V., Makishima H, Afable M, Huh J, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood [Internet]. 2009 [cited 2022 Jan 19];113(25):6403–10. Available from: https://pubmed.ncbi.nlm.nih.gov/19372255/.

  37. Jian X, Boerwinkle E, Liu X. In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res [Internet]. 2014 Dec 16 [cited 2022 Feb 13];42(22):13534. Available from: https://pubmed.ncbi.nlm.nih.gov/25416802/.

  38. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol [Internet]. 2012 [cited 2022 Jan 19];130(6):1428. Available from: https://pubmed.ncbi.nlm.nih.gov/22981790/.

  39. Sanyoura M, Lundgrin EL, Subramanian HP, Yu M, Sodadasi P, Greeley SAW, et al. Novel compound heterozygous LRBA deletions in a 6-month-old with neonatal diabetes. Diabetes Res Clin Pract [Internet]. 2021 May 1 [cited 2022 Jan 19];175. Available from: http://www.diabetesresearchclinicalpractice.com/article/S0168822721001571/fulltext.

  40. Dyer L, Li X, Denton J, Jones B, Liston E, Hilton D, et al. Gene dosage defects in primary immunodeficiencies and related disorders: a pilot study. J Transl Genet Genomics [Internet]. 2017 Dec 25 [cited 2022 Jan 19];1:23–7. Available from: https://jtggjournal.com/article/view/2333.

  41. Liu J, Liang L, Li D, Nong L, Zheng Y, Huang S, et al. JAK3/STAT3 oncogenic pathway and PRDM1 expression stratify clinicopathologic features of extranodal NK/T-cell lymphoma, nasal type. Oncol Rep [Internet]. 2019 Jun 1 [cited 2021 Dec 20];41(6):3219–32. Available from: https://pubmed.ncbi.nlm.nih.gov/31002364/.

  42. Tulstrup M, Soerensen M, Hansen JW, Gillberg L, Needhamsen M, Kaastrup K, et al. TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis. Nat Commun [Internet]. 2021 Dec 1 [cited 2021 Dec 20];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/34663818/.

  43. Klug M, Schmidhofer S, Gebhard C, Andreesen R, Rehli M. 5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes. Genome Biol [Internet]. 2013 May 26 [cited 2021 Dec 29];14(5):1–8. Available from: https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-5-r46.

  44. Xia C-Q, Peng R, Chernatynskaya A V., Yuan L, Carter C, Valentine J, et al. Increased IFN-α-producing plasmacytoid dendritic cells (pDCs) in human Th1-mediated type 1 diabetes: pDCs augment Th1 responses through IFN-α production. J Immunol [Internet]. 2014 Aug 1 [cited 2022 Apr 4];193(3):1024–34. Available from: https://pubmed.ncbi.nlm.nih.gov/24973447/.

  45. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med [Internet]. 2017 Jul 13 [cited 2022 Feb 13];377(2):111–21. Available from: https://pubmed.ncbi.nlm.nih.gov/28636844/.

  46. Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science [Internet]. 2017 Feb 24 [cited 2022 Jan 14];355(6327):842–7. Available from: https://pubmed.ncbi.nlm.nih.gov/28104796/.

  47. Yang R, Qu C, Zhou Y, Konkel JE, Shi S, Liu Y, et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity [Internet]. 2015 Aug 18 [cited 2021 Dec 29];43(2):251–63. Available from: https://pubmed.ncbi.nlm.nih.gov/26275994/.

  48. Yue X, Lio CWJ, Samaniego-Castruita D, Li X, Rao A. Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun 2019 101 [Internet]. 2019 May 1 [cited 2021 Dec 29];10(1):1–14. Available from: https://www.nature.com/articles/s41467-019-09541-y.

  49. Lam AJ, Uday P, Gillies JK, Levings MK. Helios is a marker, not a driver, of human Treg stability. Eur J Immunol [Internet]. 2022 Jan 1 [cited 2022 Apr 6];52(1):75–84. Available from: https://pubmed.ncbi.nlm.nih.gov/34561855/.

  50. Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity [Internet]. 2015 Apr 21 [cited 2021 Dec 29];42(4):613–26. Available from: https://pubmed.ncbi.nlm.nih.gov/25862091/.

  51. Furutani E, Shimamura A. Germline genetic predisposition to hematologic malignancy. J Clin Oncol [Internet]. 2017 Mar 20 [cited 2022 Jan 19];35(9):1018–28. Available from: https://pubmed.ncbi.nlm.nih.gov/28297620/.

  52. A B, E O, CM A. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med [Internet]. 2016 Apr 7 [cited 2022 Jan 19];374(14):1390–1. Available from: https://pubmed.ncbi.nlm.nih.gov/27050225/.

  53. Ferrone CK, Blydt-Hansen M, Rauh MJ. Age-associated TET2 mutations: common drivers of myeloid dysfunction, cancer and cardiovascular disease. Int J Mol Sci [Internet]. 2020 Jan 2 [cited 2021 Dec 30];21(2). Available from: https://pubmed.ncbi.nlm.nih.gov/31963585/.

  54. Neocleous V, Byrou S, Toumba M, Costi C, Shammas C, Kyriakou C, et al. Evidence of digenic inheritance in autoinflammation-associated genes. J Genet [Internet]. 2016 Dec 1 [cited 2022 Feb 15];95(4):761–6. Available from: https://pubmed.ncbi.nlm.nih.gov/27994174/.

  55. Hoyos-Bachiloglu R, Chou J, Sodroski CN, Beano A, Bainter W, Angelova M, et al. A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. J Clin Invest [Internet]. 2017 Dec 1 [cited 2022 Feb 13];127(12):4415–20. Available from: https://pubmed.ncbi.nlm.nih.gov/29106381/.

  56. Ameratunga R, Woon ST, Bryant VL, Steele R, Slade C, Leung EY, et al. Clinical implications of digenic inheritance and epistasis in primary immunodeficiency disorders. Front Immunol [Internet]. 2018 Jan 26 [cited 2022 Feb 13];8(JAN). Available from: https://pubmed.ncbi.nlm.nih.gov/29434582/.

  57. Aluri J, Cooper MA. Genetic mosaicism as a cause of inborn errors of immunity. J Clin Immunol [Internet]. 2021 May 1 [cited 2022 Feb 13];41(4):718–28. Available from: https://pubmed.ncbi.nlm.nih.gov/33864184/.

  58. Magerus-Chatinet A, Neven B, Stolzenberg MC, Daussy C, Arkwright PD, Lanzarotti N, et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Invest [Internet]. 2011 Jan 4 [cited 2020 Sep 22];121(1):106–12. Available from: https://pubmed.ncbi.nlm.nih.gov/21183795/

  59. Clementi R, Dagna L, Dianzani U, Dupré L, Dianzani I, Ponzoni M, et al. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma . N Engl J Med [Internet]. 2004 Sep 30 [cited 2020 Dec 5];351(14):1419–24. Available from: https://pubmed.ncbi.nlm.nih.gov/15459303/.

  60. Boggio E, Aricò M, Melensi M, Dianzani I, Ramenghi U, Dianzani U, et al. Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype. Pediatrics [Internet]. 2013 Oct [cited 2020 Dec 5];132(4). Available from: https://pubmed.ncbi.nlm.nih.gov/24043286/.

  61. Martínez-Feito A, Melero J, Mora-Díaz S, Rodríguez-Vigil C, Elduayen R, González-Granado LI, et al. Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation. Immunobiology [Internet]. 2016 Jan 1 [cited 2020 Sep 22];221(1):40–7. Available from: https://pubmed.ncbi.nlm.nih.gov/26323380/.

  62. Zhang Q, Casanova JL. Human TET2 bridges cancer and immunity. Blood [Internet]. 2020 Aug 27 [cited 2022 Jan 2];136(9):1018–9. Available from: https://pubmed.ncbi.nlm.nih.gov/32853377/.

  63. Vento-Tormo R, Company C, Rodríguez-Ubreva J, de la Rica L, Urquiza JM, Javierre BM, et al. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol [Internet]. 2016 [cited 2022 Jan 7];17(1). Available from: https://pubmed.ncbi.nlm.nih.gov/26758199/.

  64. Nakatsukasa H, Oda M, Yin J, Chikuma S, Ito M, Koga-Iizuka M, et al. Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. Int Immunol [Internet]. 2019 Apr 26 [cited 2022 Jan 6];31(5):335–47. Available from: https://pubmed.ncbi.nlm.nih.gov/30726915/.

  65. Yue X, Trifari S, Äijö T, Tsagaratou A, Pastor WA, Zepeda-Martínez JA, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med [Internet]. 2016 Mar 7 [cited 2022 Jan 6];213(3):377–97. Available from: https://pubmed.ncbi.nlm.nih.gov/26903244/.

  66. Someya K, Nakatsukasa H, Ito M, Kondo T, Tateda K ichi, Akanuma T, et al. Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation. Int Immunol [Internet]. 2017 Aug 1 [cited 2022 Jan 6];29(8):365–75. Available from: https://pubmed.ncbi.nlm.nih.gov/29048538/.

  67. Kim YC, Bhairavabhotla R, Yoon J, Golding A, Thornton AM, Tran DQ, et al. Oligodeoxynucleotides stabilize Helios-expressing Foxp3+ human T regulatory cells during in vitro expansion. Blood [Internet]. 2012 Mar 22 [cited 2022 Apr 7];119(12):2810–8. Available from: https://pubmed.ncbi.nlm.nih.gov/22294730/.

  68. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol [Internet]. 2011 Apr 1 [cited 2022 Apr 7];186(7):3918–26. Available from: https://pubmed.ncbi.nlm.nih.gov/21368230/.

  69. Beyer M, Schultze JL. Regulatory T cells in cancer. Blood [Internet]. 2006 Aug 1 [cited 2022 Feb 15];108(3):804–11. Available from: https://pubmed.ncbi.nlm.nih.gov/16861339/.

  70. Martín-Gayo E, Sierra-Filardi E, Corbí AL, Toribio ML. Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood [Internet]. 2010 Jul 1 [cited 2022 Apr 7];115(26):5366–75. Available from: https://pubmed.ncbi.nlm.nih.gov/20357241/.

  71. Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, et al. Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets. J Exp Med [Internet]. 2016 Jul 25 [cited 2022 Jan 19];213(8):1589–608. Available from: https://pubmed.ncbi.nlm.nih.gov/27401342/.

  72. Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol [Internet]. 2015 Oct 1 [cited 2022 Apr 20];136(4):993–1006.e1. Available from: https://pubmed.ncbi.nlm.nih.gov/26162572/.

  73. Gohil M, Jordan MS, Carty SA. TET2 regulates CD4+ T follicular helper differentiation. Blood. 2017;130(Supplement 1):3578–3578.

    Google Scholar 

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Acknowledgements

We thank Rosa Ayala for the helpful discussion and María J Díaz-Madroñero, María Victoria Pantoja, Vanesa García, and María Carmen Moreno for their technical assistance. We are very grateful for the collaboration of the family of the patient.

Funding

This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project (FIS-PI16/2053 and FIS-PI21/01119) and PI 2021/0132 to Luis M Allende and co-funded by the European Union.

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Author notes

  1. Marta López-Nevado, Javier Ortiz-Martín, and Cristina Serrano contributed equally to this work.

Authors and Affiliations

  1. Immunology Department, University Hospital 12 de Octubre, Av de Córdoba s/n, 28041, Madrid, Spain

    Marta López-Nevado, Francisco J. Gil-Etayo, Edgar Rodríguez-Frías, Oscar Cabrera-Marante, Pablo Morales-Pérez, Estela Paz-Artal & Luis M. Allende

  2. Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain

    Marta López-Nevado, Francisco J. Gil-Etayo, Edgar Rodríguez-Frías, Oscar Cabrera-Marante, Pablo Morales-Pérez, Estela Paz-Artal & Luis M. Allende

  3. Hematology Department, University Hospital La Princesa, Madrid, Spain

    Javier Ortiz-Martín & Reyes Arranz-Sáez

  4. Immunology Department, University Hospital Fundación Jiménez Díaz, Madrid, Spain

    Cristina Serrano

  5. Hematology Department, University Hospital Fundación Jiménez Díaz, Madrid, Spain

    María A. Pérez-Saez, José L. López-Lorenzo, Rocío N. Salgado-Sánchez & Ana Cerdá-Montagud

  6. Pathology Department, Research Institute Fundación Jiménez Díaz, Madrid, Spain

    María S. Rodríguez-Pinilla & Rebeca Manso

  7. Genetics Department, University Hospital 12 de Octubre, Madrid, Spain

    Juan F. Quesada-Espinosa & María J. Gómez-Rodríguez

  8. UDisGen (Unidad de Dismorfología Y Genética), University Hospital 12 de Octubre, Madrid, Spain

    Juan F. Quesada-Espinosa & María J. Gómez-Rodríguez

  9. School of Medicine, Complutense University of Madrid, Madrid, Spain

    Estela Paz-Artal & Luis M. Allende

  10. CIBERINFEC, ISCIII, Madrid, Spain

    Estela Paz-Artal

  11. Immunology Department, University Hospital La Princesa, Madrid, Spain

    Cecilia Muñoz-Calleja

  12. School of Medicine, University Autónoma de Madrid, Madrid, Spain

    Cecilia Muñoz-Calleja

  13. Research Institute Hospital de La Princesa, Madrid, Spain

    Cecilia Muñoz-Calleja

Authors
  1. Marta López-Nevado
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  2. Javier Ortiz-Martín
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  3. Cristina Serrano
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  4. María A. Pérez-Saez
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  5. José L. López-Lorenzo
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  6. Francisco J. Gil-Etayo
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  7. Edgar Rodríguez-Frías
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  14. Juan F. Quesada-Espinosa
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  15. María J. Gómez-Rodríguez
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  17. Cecilia Muñoz-Calleja
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  18. Reyes Arranz-Sáez
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  19. Luis M. Allende
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Contributions

M. L.-N. and L. M. A. contributed to conception, design of the study, and drafted the manuscript. M. L.-N. did the molecular and functional studies and analyzed the results and constructed the tables and figures. F. J. G.-E. contributed to the sample preparation, DNA, and protein extraction and functional studies. J. O.-M., C. S., M. A. P.-S., J. L. L.-L., E. R.-F., O. C.-M., C. M.-C., and R. A.-S. conducted the clinical and immunological follow-up of the patients and informed them about the study and collected the informed consents approved by the ethics committee. M. S. R.-P., R. M., R. N. S.-S., and A. C.-M. facilitated the molecular studies in the T-cell lymphomas. J. F. Q.-E. and M. J. G.-R. did the whole exome sequencing and chromosomal microarray studies. J. O. –M., C. S., C. M.-C., R. A.-S., P. M.-P., and E. P.-A. contributed to the critical review of the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Marta López-Nevado or Luis M. Allende.

Ethics declarations

Ethics Approval

All experimental work was performed under protocols approved by the Institutional Review Board (IRB) of the Institution (imas12), after written informed consent for publication of clinical and immunological information of the patients.

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All participants provided written informed consent to participate.

Consent for Publication

All participants have consented to publication of their data.

Conflict of Interest

The authors declare no competing interests.

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Cecilia Muñoz-Calleja, Reyes Arranz-Sáez, and Luis M. Allende are seniors authors who contributed equally to this work.

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López-Nevado, M., Ortiz-Martín, J., Serrano, C. et al. Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy. J Clin Immunol 43, 165–180 (2023). https://doi.org/10.1007/s10875-022-01361-y

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