CoChat
Sign Up
Cited by 15Lymphoma Diagnosis and TreatmentCytokine Signaling Pathways and InteractionsViral-associated cancers and disorders

Alterations of negative regulators of cytokine signalling in immunodeficiency‐related non‐Hodgkin lymphoma

Open access
Capello, Daniela, Gloghini, Annunziata, Baldanzi, Gianluca, Martini, Maurizio, Deambrogi, Clara, Lucioni, Marco, Piranda, Daniela, Famà, Rosella +8 more·2013·Hematological Oncology
DOI 10.1002/hon.2010
Open this paper in CoChat — free accountOpen PDF

Abstract

We investigated immunodeficiency‐related non‐Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non‐receptor type 6/Src homology 2‐containing tyrosine phosphatase‐1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B‐cell lymphoma (63%), with a higher prevalence in the non‐germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B‐cell lymphoma and polymorphic post‐transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity. Copyright © 2012 John Wiley & Sons, Ltd.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/hon.2010

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Frequent methylation in the promoter region of PTPN6 is strongly correlated with decreased PTPN6 mRNA expression and increased pSTAT3 expression in immunodeficiency-related non-Hodgkin lymphoma.

    “For instance, frequent methylation in the promoter region of PTPN6 is strongly correlated with decreased PTPN6 messenger ribonucleic acid (mRNA) expression and increased pSTAT3 expression in immunodeficiency-related non-Hodgkin lymphoma, demonstrating that epigenetic silencing of a phosphatase targeting pSTAT3 can lead to STAT3 activation.63”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [63]

    The ‘PTPN6/SHP1 is frequently methylated in subsets of ID-NHL’ section reports frequent methylation, reduced or absent PTPN6/SHP1 mRNA in methylated cases, and PY-STAT3 in some methylated cases but none of the unmethylated cases tested. The Discussion describes PY-STAT3 as preferentially associated with methylation and says silencing may sustain pathway activation; it does not demonstrate that silencing causes STAT3 activation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.

    “Conversely, activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [63]

    The Discussion (page not provided) reports that methylation and silencing of the negative regulator PTPN6/SHP1 are associated with STAT3-pathway activation in lymphomas, and suggests that this silencing may sustain activation. The paper also reports SOCS1 mutations, but does not show that genomic inactivation caused STAT3 activation in its cases. The claim therefore extends the paper’s evidence beyond epigenetic silencing in particular lymphomas. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. Tran H, Nourse J, Hall S, Green M, Griffiths L, Gandhi MK. Immunodeficiency-associated lymphomas. Blood Rev 2008; 22: 261-281.
  2. Nourse JP, Jones K, Gandhi MK. Epstein-Barr virus-related post- transplant lymphoproliferative disorders: pathogenetic insights for targeted therapy. Am J Transplant 2011; 11: 888-895.
  3. Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol 2007; 60: 1365-1372.
  4. Swerdlow SH, Campo E, Harris NL, et al (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2008.
  5. Martínez-Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol 2002; 14: 528-532.
  6. Epeldegui M, Vendrame E, Martínez-Maza O. HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma. Immunol Res 2010; 48: 72-83.
  7. Capello D, Rossi D, Gaidano G. Post-transplant lymphoproli- ferative disorders: molecular basis of disease histogenesis and pathogenesis. Hematol Oncol 2005; 23: 61-67.
  8. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003; 3: 900-911.
  9. Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007; 282: 20059-20063.
  10. Tamir I, Dal Porto JM, Cambier JC. Cytoplasmic protein tyro- sine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction. Curr Opin Immunol 2000; 12: 307-315.
  11. Ostman A, Hellberg C, Böhmer FD. Protein-tyrosine phospha- tases and cancer. Nat Rev Cancer 2006; 6: 307-320.
  12. Tsui FWL, Martin A, Wang J, Tsui HW. Investigations into the regulation and function of the SH2 domain-containing protein- tyrosine phosphatase, SHP-1. Immunol Res 2006; 35: 127-136.
  13. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signal- ling and immune regulation. Nat Rev Immunol 2007; 7: 454-465.
  14. Valentino L, Pierre J. JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 2006; 71: 713-721.
  15. Ding BB, Yu JJ, Yu RY, et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 2008; 111: 1515-1523. 27 SOCS1 and PTPN6 inactivation in ID-NHL
  16. Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood 2008; 111: 3701-3713.
  17. Wu ZL, Song YQ, Shi YF, Zhu J. High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J Hematol Oncol 2011; 4: 31.
  18. Melzner I, Bucur AJ, Brüderlein S, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 2005; 105: 2535-2542.
  19. Mottok A, Renné C, Willenbrock K, Hansmann ML, Bräuninger A. Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood 2007; 110: 3387-3390.
  20. Carbone A, Gloghini A, Larocca LM, et al. Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas. Blood 2001; 97: 744-751.
  21. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103: 275-282.
  22. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(ÀDelta Delta C(T)). Methods 2001; 25: 402-408.
  23. Oka T, Ouchida M, Koyama M, et al. Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 2002; 62: 6390-6394.
  24. Zhang Q, Raghunath PN, Vonderheid E, Odum N, Wasik MA. Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter. Am J Pathol 2000; 157: 1137-1146.
  25. Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lympho- mas. Nature 2001; 412: 341-346.
  26. Rogozin IB, Diaz M. Cutting edge: DGYW/WRCH is a better predictor of mutability at G:C bases in Ig hypermutation than the widely accepted RGYW/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered pro- cess. J Immunol 2004; 172: 3382-3384.
  27. Minoo P, Zadeh MM, Rottapel R, Lebrun JJ, Ali S. A novel SHP-1/Grb2-dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling. Blood 2004; 103: 1398-1407.
  28. Oka T, Yoshino T, Hayashi K, et al. Reduction of hematopoietic cell-specific tyrosine phosphatase SHP-1 gene expression in natural killer cell lymphoma and various types of lymphomas/ leukemias: combination analysis with cDNA expression array and tissue microarray. Am J Pathol 2001; 159: 1495-1505.
  29. Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 2004; 103: 4630-4635.
  30. Khoury JD, Rassidakis GZ, Medeiros LJ, Amin HM, Lai R. Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood 2004; 104: 1580-1581.
  31. Han Y, Amin HM, Frantz C, et al. Restoration of shp1 expres- sion by 5-AZA-2'-deoxycytidine is associated with downregula- tion of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma. Leukemia 2006; 20: 1602-1609.
  32. Delibrias CC, Floettmann JE, Rowe M, Fearon DT. Downregu- lated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes. J Exp Med 1997; 186: 1575-1583.
  33. Kossev PM, Raghunath PN, Bagg A, Schuster S, Tomaszewski JE, Wasik MA. SHP-1 expression by malignant small B-cell lymphomas reflects the maturation stage of their normal B-cell counterparts. Am J Surg Pathol 2001; 25: 949-955.
  34. Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist 2007; 12: 569-576.
  35. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 2003; 101: 1535-1542.
  36. Gasperini P, Sakakibara S, Tosato G. Contribution of viral and cellular cytokines to Kaposi's sarcoma-associated herpesvirus pathogenesis. J Leukoc Biol 2008; 84: 994-1000.
  37. Adam N, Rabe B, Suthaus J, Grötzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 re- ceptor. J Virol 2009; 83: 5117-5126.
  38. Brinkmann MM, Schulz TF. Regulation of intracellular signal- ling by the terminal membrane proteins of members of the Gammaherpesvirinae. J Gen Virol 2006; 87: 1047-1074.
  39. Nitschke L. The role of CD22 and other inhibitory co-receptors in B-cell activation. Curr Opin Immunol 2005; 17: 290-297.
  40. Alexander WS, Starr R, Fenner JE, et al. SOCS1 is a critical inhibitor of interferon-g signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98: 597-608.
  41. Marine JC, Topham DJ, McKay C, et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 1999; 98: 609-616.
  42. Roberts AW, Robb L, Rakar S, et al. Placental defects and em- bryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc Natl Acad Sci 2001; 98: 9324-9329.
  43. Le Y, Zhu BM, Harley B, et al. SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling path- way during B lymphopoiesis. Immunity 2007; 27: 811-823.
  44. Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non- Hodgkin lymphoma. Blood 2003; 102: 1833-1841.
  45. Capello D, Rasi S, Oreste P, et al. Molecular characterization of post-transplant lymphoproliferative disorders of donor origin occurring in liver transplant recipients. J Pathol 2009; 218: 478-486.
  46. Cerri M, Capello D, Muti G, et al. Aberrant somatic hypermuta- tion in post-transplant lymphoproliferative disorders. Br J Haematol 2004; 127: 362-364.
  47. Brender C, Lovato P, Sommer VH, et al. Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha. Leukemia 2005; 19: 209-213.
  48. Kaplan DH, Shankaran V, Dighe AS, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad USA 1998; 95: 7556-7561.
  49. Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol 2009; 9: 235-245.
  50. Sammicheli S, Dang Vu Phuong L, Ruffin N, et al. IL-7 pro- motes CD95-induced apoptosis in B cells via the IFN-g/STAT1 pathway. PLoS One 2011; 6: e28629.
  51. Bishton M, Kenealy M, Johnstone R, Rasheed W, Prince HM. Epigenetic targets in hematological malignancies: combination therapies with HDACis and demethylating agents. Expert Rev Anticancer Ther 2007; 7: 1439-1449.
  52. Capello D, Gloghini A, Martini M, et al. Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non- Hodgkin lymphomas. Br J Haematol 2011; 152: 777-780.
  53. Rinaldi A, Capello D, Scandurra M, et al. Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma. Br J Haematol 2010; 149: 569-577.
  54. Capello D, Scandurra M, Poretti G, et al. Genome wide DNA- profiling of HIV-related B-cell lymphomas. Br J Haematol 2010; 148: 245-255.

Cited by

Sorted by citations

Authors
Capello, D., Gloghini, A., Baldanzi, G., Martini, M., Deambrogi, C., Lucioni, M., Piranda, D., Famà, R., Graziani, A., Spina, M., Tirelli, U., Paulli, M., Larocca, L. M., Gaidano, G., Carbone, A., & Sinigaglia, F.
Affiliations
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • University of Pavia (IT)
  • Centro di Riferimento Oncologico (IT)
  • Division of Hematology ‘Amedeo Avogadro’ University of Eastern Piedmont Novara Italy
Corresponding author
Capello, Daniela
ORCID
Venue
Hematological Oncology
Publisher
Wiley
Published
2012-04-09
Volume
31
Issue
1
Pages
22-28
ISSN
  • 0278-0232 (ISSN-L)
  • 1099-1069
DOI
10.1002/hon.2010
OpenAlex
W1484333478
Cited by
15
References
1
Citations by year
2022: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 1
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Hematological Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders
  • Ministero della Salute
  • Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2008)
  • Regione Piemonte
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
Keywords
primary effusion lymphoma, diffuse large B-cell lymphoma, epigenetic silencing, SHP2, SOCS1, SOCS3, JAK/STAT3 signaling, cytokine signaling, somatic hypermutation, post-transplant lymphoproliferative disorder, molecular alterations
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, DNA Mutational Analysis, DNA, Neoplasm, Humans, Lymphoproliferative Disorders, Mutation, Neoplasm Proteins, Postoperative Complications, Retrospective Studies, Signal Transduction, Cytokines, Organ Transplantation, Lymphoma, AIDS-Related, Immunocompromised Host, DNA Methylation, Cell Line, Tumor, STAT Transcription Factors, Suppressor of Cytokine Signaling Proteins, Janus Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Clonal Evolution

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review