CoChat
Sign Up
Cited by 151Myeloproliferative Neoplasms: Diagnosis and TreatmentLymphoma Diagnosis and TreatmentChronic Lymphocytic Leukemia Research

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy

Open access
Porpaczy, Edit, Tripolt, Sabrina, Hoelbl-Kovacic, Andrea, Gisslinger, Bettina, Bago-Horvath, Zsuzsanna, Casanova-Hevia, Emilio, Clappier, Emmanuelle, Decker, Thomas +29 more·2018·Blood
DOI 10.1182/blood-2017-10-810739PMC PMC7115916
Open this paper in CoChat — free accountOpen PDF

Abstract

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1−/− mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

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 · 10.1182/blood-2017-10-810739

Cites

2 of 2 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?

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: 55

  1. [2]Vannucchi AM Kiladjian JJ Griesshammer M Ruxolitinib versus standard therapy for the treatment of polycythemia vera N Engl J Med 2015 372 5 426 435 25629741 PMC4358820
  2. [3]Harrison C Kiladjian J-J Al-Ali HK JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis N Engl J Med 2012 366 9 787 798 22375970
  3. [4]Tefferi A Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms N Engl J Med 2012 366 9 844 846 22375977
  4. [5]Rajala HLM Eldfors S Kuusanmaki H Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia Blood 2013 121 22 4541 4550 23596048 PMC3668487
  5. [6]Koskela HLM Eldfors S Ellonen P Somatic STAT3 mutations in large granular lymphocytic leukemia N Engl J Med 2012 366 20 1905 1913 22591296 PMC3693860
  6. [7]Skoda RC Duek A Grisouard J Pathogenesis of myeloproliferative neoplasms Exp Hematol 2015 43 8 599 608 26209551
  7. [8]Vannucchi AM Masala G Antonioli E Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms Cancer Epidemiol Biomarkers Prev 2009 18 7 2068 2073 19531676
  8. [9]Masarova L Newberry KJ Pierce SA Association of lymphoid malignancies and Philadelphia-chromosome negative myelo-proliferative neoplasms: Clinical characteristics, therapy and outcome Leuk Res 2015 39 8 822 827 26012362 PMC4547830
  9. [10]Frederiksen H Christiansen CF Hasselbalch HC Sorensen HT Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study Blood 2016 118 25 6515 6521 22039256
  10. [11]Palandri F Derenzini E Ottaviani E Association of essential thrombocythemia and non-Hodgkin lymphoma: a single-centre experience Leuk Lymphoma 2009 50 3 481 484 19241208
  11. [12]Rumi E Passamonti F Elena C Increased risk of lymphoid neoplasm in patients with myeloproliferative neoplasm: a study of 1,915 patients Haematologica 2011 96 3 454 458 21109692 PMC3046278
  12. [13]Bhatt VR Bociek RG Yuan J Leukemic diffuse large B-cell lymphoma in a patient with myeloproliferative disorder J Natl Compr Canc Netw 2015 13 3 281 287 25736004
  13. [14]Tefferi A Pardanani A Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis Mayo Clin Proc 2011 86 12 1188 1191 22034658 PMC3228619
  14. [15]Lesinski GB Anghelina M Zimmerer J The antitumor effects of IFN-alpha are abrogated in a STAT1-deficient mouse J Clin Invest 2003 112 2 170 180 12865406 PMC164283
  15. [16]Lee CK Smith E Gimeno R Gertner R Levy DE STAT1 affects lymphocyte survivaland proliferation partially independent of its role downstream of IFN-gamma J Immunol 2000 164 3 1286 1292 10640742
  16. [17]Hannesdottir L DaschilN, Philipp S MMTV-neu mice deficient in STAT1 are susceptible to develop ovarian teratomas Int J Dev Biol 2012 56 4 279 283 22562203
  17. [18]Klover PJ Muller WJ Robinson GW Pfeiffer RM Yamaji D Hennighausen L Loss of STAT1 from mouse mammary epithelium results in an increased Neu-induced tumor burden Neoplasia 2010 12 11 899 905 21076615 PMC2978912
  18. [19]Raven JF Williams V Wang S Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation Cell Cycle 2011 10 5 794 804 21311224
  19. [20]Chen E Beer PA Godfrey AL Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling Cancer Cell 2010 18 5 524 535 21074499 PMC2996868
  20. [21]van Dongen JJM LangerakAW, Bmggemann M 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 2317 14671650
  21. [22]Ghia P Stamatopoulos K Belessi C European Research Initiative on CLL ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia Leukemia 2007 21 1 1 3 17167526
  22. [23]Duez M Giraud M Herbert R Rocher T Salson M Thonier F Vidjil: a web platform for analysis of high-throughput repertoire sequencing PLoS One 2016 11 11 e0166126 27835690 PMC5106020
  23. [25]He J Abdel-Wahab O Nahas MK Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting Blood 2016 127 24 3004 3014 26966091 PMC4968346
  24. [26]Durbin JE Hackenmiller R Simon MC Levy DE Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease Cell 1996 84 3 443 450 8608598
  25. [27]Colucci F Soudais C Rosmaraki E Vanes L Tybulewicz VL Di Santo JP Dissecting NK cell development using a novel alymphoid mouse model: investigating the role of the c-abl proto-oncogene in murine NK cell differentiation J Immunol 1999 162 5 2761 2765 10072522
  26. [28]Kovacic B Stoiber D Moriggl R STAT1 acts as a tumor promoter for leukemia development Cancer Cell 2006 10 1 77 87 16843267
  27. [29]Berger A Hoelbl-Kovacic A Bourgeais J PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis Leukemia 2014 28 3 629 641 24263804 PMC3948164
  28. [30]Chang Y Paige CJ Wu GE Enumeration and characterization of DJH structures in mouse fetal liver EMBO J 1992 11 5 1891 1899 1582417 PMC556647
  29. [31]Dobin A Davis CA Schlesinger F STAR: ultrafast universal RNA-seq aligner Bioinformatics 2013 29 1 15 21 23104886 PMC3530905
  30. [32]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol 2014 15 12 550 25516281 PMC4302049
  31. [33]Metsalu T Vilo J ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap Nucleic Acids Res 2015 43 W1 W566 W570 25969447 PMC4489295
  32. [34]Bauer S Grossmann S Vingron M Robinson PN Ontologizer 2.0-a multifunctional tool for GO term enrichment analysis and data exploration Bioinformatics 2008 24 14 1650 1651 18511468
  33. [35]Tefferi A Lasho TL Guglielmelli P Targeted deep sequencing in polycythemia vera and essential thrombocythemia Blood Adv 2016 1 1 21 30 29296692 PMC5744051
  34. [36]Guglielmelli P Lasho TL Rotunno G The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients Leukemia 2014 28 9 1804 1810 24549259
  35. [37]Tefferi A Guglielmelli P Lasho TL CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients Leukemia 2014 28 7 1494 1500 24496303
  36. [38]Shipp MA Harrington DP Anderson JR International Non-Hodgkin's Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin's lymphoma N Engl J Med 1993 329 14 987 994 8141877
  37. [39]Zhang N-N Shen S-H Jiang L-J RIG-I plays a critical role in negatively regulating granulocytic proliferation Proc Natl Acad Sci USA 2008 105 30 10553 10558 18650396 PMC2492484
  38. [40]Swerdlow SH Campo E Pileri SA The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016 127 20 2375 2390 26980727 PMC4874220
  39. [41]Popov VM Dobrea CM Popescu M Diffuse large B-cell lymphoma and polycythemia vera discovered at the onset - a rare association and its possible importance in lymphoma prognosis Rom J Morphol Embryol 2016 57 1 313 318 27151728
  40. [42]Assouan D Lebon D Charbonnier A Royer B Marolleau JP Gruson B Ruxolitinib as a promising treatment for corticosteroidrefractory graft-versus-host disease Br J Haematol 2018 181 5 687 689 28444730
  41. [43]Betts BC Bastian D Iamsawat S Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation Proc Natl Acad Sci USA 2018 115 7 1582 1587 29382747 PMC5816153
  42. [44]Keohane C Kordasti S Seidl T JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells Br J Haematol 2015 171 1 60 73 26075866
  43. [45]Linke-Serinsoz E Fend F Quintanilla-Martinez L Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) related lymphomas, pathology view point Semin Diagn Pathol 2017 34 4 352 363 28506687
  44. [46]Low LK Song JY B-cell lymphoproliferative disorders associated with primary and acquired immunodeficiency Surg Pathol Clin 2016 9 1 55 77 26940268
  45. [47]Kim H-J Ko YH Kim JE Hematopathology Study Group of the Korean Society of Pathologists. Epstein-Barr virus-associated lymphoproliferative disorders: review and update on 2016 WHO classification J Pathol Transl Med 2017 51 4 352 358 28592786 PMC5525035
  46. [48]Khandelwal P Teusink-Cross A Davies SM Ruxolitinib as salvage therapy in steroidrefractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients Biol Blood Marrow Transplant 2017 23 7 1122 1127 28344057
  47. [49]Petrara MR Giunco S Serraino D Dolcetti R De Rossi A Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment Cancer Lett 2015 369 1 37 44 26279520
  48. [50]Pajor L Lacza A Kereskai L Increased incidence of monoclonal B-cell infiltrate in chronic myeloproliferative disorders Mod Pathol 2004 17 12 1521 1530 15257312
  49. [51]Pardanani A Lasho TL Finke C Extending Jak2V617Fand MplW515 mutation analysis to single hematopoietic colonies and B and T lymphocytes Stem Cells 2007 25 9 2358 2362 17540852
  50. [52]Larsen TS Christensen JH Hasselbalch HC Pallisgaard N The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders Br J Haematol 2007 136 5 745 751 17313377
  51. [53]Nangalia J Green AR Myeloproliferative neoplasms: from origins to outcomes Blood 2017 130 23 2475 2483 29212804
  52. [54]Fallarino F Gajewski TF Cutting edge: differentiation of antitumor CTL in vivo requires host expression of Stat1 J Immunol 1999 163 8 4109 4113 10510345
  53. [55]Nishibori T Tanabe Y Su L David M Impaired development of CD41 CD251 regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease J Exp Med 2004 199 1 25 34 14699080 PMC1193645
  54. [56]Badgwell B Lesinski GB Magro C Abood G Skaf A Carson W III The antitumor effects of interferon-alpha are maintained in mice challenged with a STAT1-deficient murine melanoma cell line J Surg Res 2004 116 1 129 136 14732359
  55. [57]Jiang L-J Zhang N-N Ding F RA-inducible gene-I induction augments STAT1 activation to inhibit leukemia cell proliferation Proc Natl Acad Sci USA 2011 108 5 1897 1902 21224412 PMC3033283

Cited by

Sorted by citations

Authors
Porpaczy, E., Tripolt, S., Hoelbl-Kovacic, A., Gisslinger, B., Bago-Horvath, Z., Casanova-Hevia, E., Clappier, E., Decker, T., Fajmann, S., Fux, D. A., Greiner, G., Gueltekin, S., Heller, G., Herkner, H., Hoermann, G., Kiladjian, J.-J., Kolbe, T., Kornauth, C., Krauth, M.-T., Kralovics, R., Muellauer, L., Mueller, M., Prchal-Murphy, M., Putz, E. M., Raffoux, E., Schiefer, A.-I., Schmetterer, K., Schneckenleithner, C., Simonitsch-Klupp, I., Skrabs, C., Sperr, W. R., Staber, P. B., Strobl, B., Valent, P., Jaeger, U., Gisslinger, H., & Sexl, V.
Affiliations
  • Comprehensive Cancer Center Vienna (AT)
  • University of Veterinary Medicine Vienna (AT)
  • Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria;
  • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria;
  • Centre National de la Recherche Scientifique (FR)
  • Max Perutz Labs (AT)
  • Department of Laboratory Medicine,
  • Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
  • Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center,
  • Department of Emergency Medicine, and
  • Munich Leukemia Laboratory (Germany) (DE)
  • Inserm (FR)
  • Medical University of Vienna (AT)
  • Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria;
  • Assistance Publique – Hôpitaux de Paris (FR)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2018-08-16
Volume
132
Issue
7
Pages
694-706
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2017-10-810739
PMC
PMC7115916
OpenAlex
W2808491541
Cited by
151
References
2
Citations by year
2026: 2 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 19 · 2021: 29 · 2020: 30 · 2019: 33 · 2018: 6
FWCI
13.89
Type
journal article
Language
en
Update notices
erratum (2019-02-14)
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
JAK1/2 inhibitor, myelofibrosis, aggressive B-cell lymphoma, myeloproliferative neoplasms, drug-induced lymphoma, clonal immunoglobulin gene rearrangement, STAT1-deficient mice, MYC expression, risk stratification
MeSH terms
Animals, Female, Humans, Neoplasm Proteins, Retrospective Studies, Lymphoma, B-Cell, Mice, Knockout, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Janus Kinase 1, Janus Kinase 2, Primary Myelofibrosis

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