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Myelodysplastic syndrome

Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML


Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous neoplasm in which JAK2 inhibition has demonstrated reductions in inflammatory cytokines and promising clinical activity. We hypothesize that annotation of inflammatory cytokines may uncover mutation-independent cytokine subsets associated with novel CMML prognostic features. A Luminex cytokine profiling assay was utilized to profile cryopreserved peripheral blood plasma from 215 CMML cases from three academic centers, along with center-specific, age-matched plasma controls. Significant differences were observed between CMML patients and healthy controls in 23 out of 45 cytokines including increased cytokine levels in IL-8, IP-10, IL-1RA, TNF-α, IL-6, MCP-1/CCL2, hepatocyte growth factor (HGF), M-CSF, VEGF, IL-4, and IL-2RA. Cytokine associations were identified with clinical and genetic features, and Euclidian cluster analysis identified three distinct cluster groups associated with important clinical and genetic features in CMML. CMML patients with decreased IL-10 expression had a poor overall survival when compared to CMML patients with elevated expression of IL-10 (P = 0.017), even when adjusted for ASXL1 mutation and other prognostic features. Incorporating IL-10 with the Mayo Molecular Model statistically improved the prognostic ability of the model. These established cytokines, such as IL-10, as prognostically relevant and represent the first comprehensive study exploring the clinical implications of the CMML inflammatory state.

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  1. 1.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

  2. 2.

    Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33:451–8.

  3. 3.

    Elena C, Galli A, Such E, Meggendorfer M, Germing U, Rizzo E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128:1408–17.

  4. 4.

    Ball M, List AF, Padron E. When clinical heterogeneity exceeds genetic heterogeneity: thinking outside the genomic box in chronic myelomonocytic leukemia. Blood. 2016;128:2381–7.

  5. 5.

    Merlevede J, Droin N, Qin T, Meldi K, Yoshida K, Morabito M, et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat Commun. 2016;7:10767.

  6. 6.

    Deininger MWN, Tyner JW, Solary E. Turning the tide in myelodysplastic/myeloproliferative neoplasms. Nat Rev Cancer. 2017;17:425–40.

  7. 7.

    Beran M, Wen S, Shen Y, Onida F, Jelinek J, Cortes J, et al. Prognostic factors and risk assessment in chronic myelomonocytic leukemia: validation study of the M.D. Anderson Prognostic Scoring System. Leuk Lymphoma. 2007;48:1150–60.

  8. 8.

    Aul C, Gattermann N, Heyll A, Germing U, Derigs G, Schneider W. Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia. 1992;6:52–9.

  9. 9.

    Worsley A, Oscier DG, Stevens J, Darlow S, Figes A, Mufti GJ, et al. Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br J Haematol. 1988;68:17–21.

  10. 10.

    Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99:840–9.

  11. 11.

    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

  12. 12.

    Padron E, Garcia-Manero G, Patnaik MM, Itzykson R, Lasho T, Nazha A, et al. An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J. 2015;5:e333.

  13. 13.

    Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28:3858–65.

  14. 14.

    Palomo L, Garcia O, Arnan M, Xicoy B, Fuster F, Cabezon M, et al. Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features. Oncotarget. 2016;7:57021–35.

  15. 15.

    Gelsi-Boyer V, Trouplin V, Roquain J, Adelaide J, Carbuccia N, Esterni B, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151:365–75.

  16. 16.

    Cui Y, Tong H, Du X, Li B, Gale RP, Qin T, et al. Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia. Exp Hematol Oncol. 2015;4:14.

  17. 17.

    Patnaik MM, Padron E, LaBorde RR, Lasho TL, Finke CM, Hanson CA, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia. 2013;27:1504–10.

  18. 18.

    Lin Y, Zheng Y, Wang ZC, Wang SY. Prognostic significance of ASXL1 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: a meta-analysis. Hematology. 2016;21:454–61.

  19. 19.

    Padron E, Dezern A, Andrade-Campos M, Vaddi K, Scherle P, Zhang Q, et al. A multi-institution phase I trial of ruxolitinib in patients with chronic myelomonocytic leukemia (CMML). Clin Cancer Res. 2016;22:3746–54.

  20. 20.

    Geissler K, Jager E, Barna A, Sliwa T, Knobl P, Schwarzinger I, et al. In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia. Eur J Haematol. 2016;97:562–7.

  21. 21.

    Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19:4399–413.

  22. 22.

    Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117–27.

  23. 23.

    Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115:5232–40.

  24. 24.

    Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29:1356–63.

  25. 25.

    Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112–21.

  26. 26.

    Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121:5068–77.

  27. 27.

    Fraley CRA, Murphy TB, Scrucca L. mclust version 4 for R: normal mixture modeling for model-based clustering, classification, and density estimation. Technical Report No. 597, Department of Statistics, University of Washington. 2012.

  28. 28.

    Raftery CFaAE. Model-based clustering, discriminant analysis and density estimation. J Am Stat Assoc. 2002;97:611–31.

  29. 29.

    CB HousemanEA, Yeh RF, Marsit CJ, Karagas MR, Wrensch M, Nelson HH, Wiemels J, Zheng S, Wiencke JK, Kelsey KT. Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions. BMC Bioinformatics. 2008;9:365.

  30. 30.

    Mirantes C, Passegue E, Pietras EM. Pro-inflammatory cytokines: emerging players regulating HSC function in normal and diseased hematopoiesis. Exp Cell Res. 2014;329:248–54.

  31. 31.

    Bender S, Haubeck HD, Van de Leur E, Dufhues G, Schiel X, Lauwerijns J, et al. Interleukin-1 beta induces synthesis and secretion of interleukin-6 in human chondrocytes. FEBS Lett. 1990;263:321–4.

  32. 32.

    Guerne PA, Carson DA, Lotz M. IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro. J Immunol. 1990;144:499–505.

  33. 33.

    Lotz M, Terkeltaub R, Villiger PM. Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. J Immunol. 1992;148:466–73.

  34. 34.

    Pulsatelli L, Dolzani P, Piacentini A, Silvestri T, Ruggeri R, Gualtieri G, et al. Chemokine production by human chondrocytes. J Rheumatol. 1999;26:1992–2001.

  35. 35.

    Honorati MC, Bovara M, Cattini L, Piacentini A, Facchini A. Contribution of interleukin 17 to human cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthr Cartil. 2002;10:799–807.

  36. 36.

    Meldi K, Qin T, Buchi F, Droin N, Sotzen J, Micol JB, et al. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest. 2015;125:1857–72.

  37. 37.

    Germing U, Strupp C, Aivado M, Gattermann N. New prognostic parameters for chronic myelomonocytic leukemia. Blood. 2002;100:731–2. author reply 2-3

  38. 38.

    Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525:389–93.

  39. 39.

    Bird L. Inflammation: TET2: the terminator. Nat Rev Immunol. 2015;15:598.

  40. 40.

    Feng X, Scheinberg P, Wu CO, Samsel L, Nunez O, Prince C, et al. Cytokine signature profiles in acquired aplastic anemia and myelodysplastic syndromes. Haematologica. 2011;96:602–6.

  41. 41.

    Boulland ML, Meignin V, Leroy-Viard K, Copie-Bergman C, Briere J, Touitou R, et al. Human interleukin-10 expression in T/natural killer-cell lymphomas: association with anaplastic large cell lymphomas and nasal natural killer-cell lymphomas. Am J Pathol. 1998;153:1229–37.

  42. 42.

    Nemunaitis J, Fong T, Shabe P, Martineau D, Ando D. Comparison of serum interleukin-10 (IL-10) levels between normal volunteers and patients with advanced melanoma. Cancer Invest. 2001;19:239–47.

  43. 43.

    Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015;367:103–7.

  44. 44.

    Mocellin S, Marincola F, Rossi CR, Nitti D, Lise M. The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev. 2004;15:61–76.

  45. 45.

    Kasamatsu T, Saitoh T, Minato Y, Shimizu H, Yokohama A, Tsukamoto N, et al. Polymorphisms of IL-10 affect the severity and prognosis of myelodysplastic syndrome. Eur J Haematol. 2016;96:245–51.

  46. 46.

    Torisu-Itakura H, Lee JH, Huynh Y, Ye X, Essner R, Morton DL. Monocyte-derived IL-10 expression predicts prognosis of stage IV melanoma patients. J Immunother. 2007;30:831–8.

  47. 47.

    Vahl JM, Friedrich J, Mittler S, Trump S, Heim L, Kachler K, et al. Interleukin-10-regulated tumour tolerance in non-small cell lung cancer. Br J Cancer. 2017;117:1644–55.

  48. 48.

    Clerici M, Merola M, Ferrario E, Trabattoni D, Villa ML, Stefanon B, et al. Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection. J Natl Cancer Inst. 1997;89:245–50.

  49. 49.

    Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, et al. IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012;72:3570–81.

  50. 50.

    Geissler K, Ohler L, Fodinger M, Virgolini I, Leimer M, Kabrna E, et al. Interleukin 10 inhibits growth and granulocyte/macrophage colony-stimulating factor production in chronic myelomonocytic leukemia cells. J Exp Med. 1996;184:1377–84.

  51. 51.

    Pochlauer S, Jager E, Jager U, Geissler K. Recombinant human interleukin-10 in patients with chronic myelomonocytic leukemia. Ann Hematol. 2014;93:1775–6.

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This research was supported in part by the USF GME Research Grant. Research was funded by EP.

Author contributions

Conception and design: EP and ES; administrative support: EP; provision of study materials or patients: ES, EP, VS, and MWD; collection and assembly of data: ADP, SN, NL, J-MZ, BF, SS, MB, MB, JR, CC, and EP; data analysis and interpretation: MWD, EP, BLF, J-MZ, SN, NL, MB, and JR.

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Correspondence to Eric Padron.

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The authors declare that they have no conflict of interest.

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