Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012, 156(4):291-301 | DOI: 10.5507/bp.2012.108

The role of cytokines in acute myeloid leukemia: A systematic review

Tomas Kupsaa,b, Jan Milos Horaceka,b, Ladislav Jebavya,b
a Department of Internal Medicine, University of Defence, Faculty of Military Health Sciences in Hradec Kralove, Czech Republic
b 4th Department of Internal Medicine - Hematology, Faculty of Medicine, Charles University in Prague, University Hospital in Hradec Kralove

Background: Acute myeloid leukemia (AML) shows a high degree of heterogeneity owing to a variety of mutations and the mechanisms of leukemogenesis. This heterogeneity is often not reflected in standard treatment approaches which while providing predictable outcomes in the majority of patients fail in particular cases even with high-dose multiagent chemotherapy regimens. Further, the unselective effect of chemotherapy leads to high treatment-related toxicity and the enormous risk of infection during prolonged pancytopenia, preventing further dose escalation.

Objectives: Cytokines play a role in leukemogenesis, AML cell persistence and treatment outcome. In this review we highlight cytokine dependent mechanisms essential for AML cell survival and the role of single cytokines in leukemogenesis and allogeneic transplantation-related phenomena. Cytokine-related mechanisms of leukemogenesis, AML cell persistence and resistance to chemotherapy are complex. Modulation of the cytokine network can disrupt signalling pathway activation and overcome the high resistance to treatment. It may also increase the selectivity of AML treatment, reduce the overall treatment-related toxicity and improve outcomes of AML treatment in all age groups of patients.

Conclusions: This review provides a deeper insight into these processes with focus on the most vulnerable step. Special attention is paid to the possibility of selective influence on defined cell populations for therapeutic target. We believe that modulating cytokine-dependent processes in AML is an approach that could be included in standard chemotherapeutic regimens for improving overall treatment outcome.

Keywords: AML, cytokines, leukemogenesis, prognosis, treatment approaches

Received: August 14, 2012; Accepted: December 3, 2012; Prepublished online: December 7, 2012; Published: December 12, 2012  Show citation

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Kupsa, T., Milos Horacek, J., & Jebavy, L. (2012). The role of cytokines in acute myeloid leukemia: A systematic review. Biomedical papers156(4), 291-301. doi: 10.5507/bp.2012.108
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References

  1. Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, McCredie KB, Gehan EA, Freireich EJ. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988;2(7):403-12. Go to PubMed...
  2. Fenaux P, Preudhomme C, Lai JL, Morel P, Beuscart R, Bauters F. Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases. Br J Haematol 1989;73(1):61-7. Go to original source... Go to PubMed...
  3. Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemeijer AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J. Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 1997;80(11 Suppl):2191-8. Go to original source... Go to PubMed...
  4. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100(13):4325-36. Go to original source... Go to PubMed...
  5. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, Wheatley K, Burnett AK, Goldstone AH. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98(5):1312-20. Go to original source... Go to PubMed...
  6. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Dohner H. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. N Eng J Med 2008;358(1):1909-18. Go to original source... Go to PubMed...
  7. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917):860-7. Go to original source... Go to PubMed...
  8. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357(9255):539-45. Go to original source... Go to PubMed...
  9. Zeh HJ, Winikoff S, Landsittel DP, Gorelik E, Marrangoni AM, Velikokhatnaya L, Winans MT, Lee K, Moser A, Bartlett D, Lotze MT, Siegfried JM, Whitcomb D, Papacristou G, Slivka A, Bigbee WL, Lokshin AE. Multianalyte profiling of serum cytokines for detection of pancreatic cancer. Cancer Biomark 2005;1(6):259-69. Go to original source...
  10. Linkov F, Lisovich A, Yurkovetsky Z, Marrangoni A, Velikokhatnaya L, Nolen B, Winans M, Bigbee WL, Siegfried J, Lokshin AE, Ferris RL. Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling. Cancer Epidemiol Biomarkers Prev 2007;16(1):102-7. Go to original source... Go to PubMed...
  11. Lambeck AJ, Crijns AP, Leffers N, Sluiter WJ, ten Hoor KA, Braid M, van der Zee AG, Daemen T, Nijman HW, Kast WM. Serum cytokine profiling as a diagnostic and prognostic tool in ovarian cancer: a potential role for interleukin 7. Clin Cancer Res 2007;13(8):2385-91. Go to original source... Go to PubMed...
  12. Kornblau SM, Tibes R, Qiu YH, Chen W, Kantarjian HM, Andreeff M, Coombes KR, Mills GB. Functional proteomic profiling of AML predicts response and survival. Blood 2009;113(1):154-64. Go to original source... Go to PubMed...
  13. Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008;111(9):4797-808. Go to original source... Go to PubMed...
  14. Loriaux MM, Levine RL, Tyner JW, Frohling S, Scholl C, Stoffregen EP, Wernig G, Erickson H, Eide CA, Berger R, Bernard OA, Griffin JD, Stone RM, Lee B, Meyerson M, Heinrich MC, Deininger MW, Gilliland DG, Druker BJ. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood 2008;111(9):4788-96. Go to original source... Go to PubMed...
  15. Van Etten RA. Aberrant cytokine signaling in leukemia. Oncogene 2007;26(47):6738-49. Go to original source... Go to PubMed...
  16. Hsu HC, Lee YM, Tsai WH, Jiang ML, Ho CH, Ho CK, Wang SY. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome. Oncology 2002;63(1):64-9. Go to original source... Go to PubMed...
  17. Dokter WH, Tuyt L, Sierdsema SJ, Esselink MT, Vellenga E. The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. Leukemia 1995;9(3):425-32. Go to PubMed...
  18. Griffin JD, Rambaldi A, Vellenga E, Young DC, Ostapovicz D, Cannistra SA. Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors. Blood 1987;70(4):1218-21. Go to original source...
  19. Birkenkamp KU, Esselink MT, Kruijer W, Vellenga E. Differential effects of interleukin-3 and interleukin-1 on the proliferation and interleukin-6 protein secretion of acute myeloid leukemic cells; the involvement of ERK, p38 and STAT5. Eur Cytokine Netw 1999;10(4):479-90.
  20. Bruserud Ø, Ryningen A, Olsens AM, Stordrange L, Øyan AM, Kalland KH, Gjertsen BT. Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica 2007;92(3):332-41. Go to original source... Go to PubMed...
  21. Krejsek J. Imunitni system jako informacni soustava. In: Krejsek J, Kopecky O. Klinicka imunologie. Nukleus HK, 2004, p. 55-69.
  22. Estrov Z, Roifman C, Mills G, Grunberger T, Gelfand EW, Freedman MH. The regulatory role of interleukin 2-responsive T lymphocytes on human marrow granulopoiesis. Blood 1987;69(4):1161-6. Go to original source...
  23. Ferrajoli A, Talpaz M, Zipf TF, Hirsch-Ginsberg C, Estey E, Wolpe SD, Estrov Z. Inhibition of acute myelogenous leukemia progenitor proliferation by macrophage inflammatory protein 1-alpha. Leukemia 1994;8(5):798-805. Go to PubMed...
  24. Estrov Z, Kurzrock R, Estey E, Wetzler M, Ferrajoli A, Harris D, Blake M, Gutterman JU, Talpaz M. Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors. Blood 1992;79(8):1938-45. Go to original source...
  25. Estrov Z, Black RA, Sleath PR, Harris D, Van Q, LaPushin R, Estey EH, Talpaz M. Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation. Blood 1995;86(12):4594-602. Go to original source...
  26. Rombouts WJC, Lowenberg B, van Putten WLJ, Ploemacher RE. Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myelogenous leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene. Leukemia 2001;15(7):1046-53. Go to original source... Go to PubMed...
  27. Tsimberidou AM, Estey E, Wen S, Pierce S, Kantarjian H, Albitar M, Kurzrock R. The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer 2008;113(7):1605-13. Go to original source... Go to PubMed...
  28. Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, Latagliata R, Mariani G, Rossini A, Battistini A, Lo-Coco F, Peschle C. Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood 2002;100(8):2980-8. Go to original source... Go to PubMed...
  29. Leverrier Y, Thomas J, Perkins GR, Mangeney M, Collins MK, Marvel J. In bone marrow derived Baf-3 cells, inhibition of apoptosis by IL-3 is mediated by two independent pathways. Oncogene 1997;14(4):425-30. Go to original source... Go to PubMed...
  30. Shimamura A, Ballif BA, Richards SA, Blenis J. Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol 2000;10(3):127-35. Go to original source... Go to PubMed...
  31. Deng X, Ruvolo P, Carr B, May WS Jr. Survival function of ERK1/2 as IL-3-activated, staurosporine resistant Bcl2 kinases. Proc Natl Acad Sci U S A 2000;97(4):1578-83. Go to original source... Go to PubMed...
  32. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997;278(5338):687-9. Go to original source... Go to PubMed...
  33. Mathieu AL, Gonin S, Leverrier Y, Blanquier B, Thomas J, Dantin C, Martin G, Baverel G, Marvel J. Activation of the phosphatidylinositol 3-kinase/Akt pathway protects against interleukin-3 starvation but not DNA damageinduced apoptosis. J Biol Chem 2001;276(14):10935-42. Go to original source... Go to PubMed...
  34. Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD, Korsemeyer SJ. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 1999;3(4):413-22. Go to original source... Go to PubMed...
  35. Dumon S, Santos SC, Debierre-Grockiego F, Gouilleux-Gruart V, Cocault L, Boucheron C, Mollat P, Gisselbrecht S, Gouilleux F. IL-3 dependent regulation of Bcl-XL gene expression by STAT5 in bone marrow derived cell line. Oncogene 1999;18(29):4191-9. Go to original source... Go to PubMed...
  36. Schepers H, van Gosliga D, Wierenga ATJ, Eggen BJL, Schuringa JJ, Vellenga E. STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood 2007;110(8):2880-8. Go to original source... Go to PubMed...
  37. Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, Estey EH, Andreeff M. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 2006;108(7):2358-65. Go to original source... Go to PubMed...
  38. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, Naoe T. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000;19(5):624-31. Go to original source... Go to PubMed...
  39. Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, Gilliland DG. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood2006;108(4):1339-45. Go to original source... Go to PubMed...
  40. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, Iino T, Rocnik JL, Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka K, Nagafuji K, Mizuno S, Niiro H, Gilliland DG, Akashi K. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood 2009;114(24):5034-43. Go to original source... Go to PubMed...
  41. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL. Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5-dependent Expression of Bcl-xL. J Exp Med 2000;191(6):977-84. Go to original source... Go to PubMed...
  42. Fajtova M, Babusikova O. Immunophenotype characterization of hematopoietic stem cells, progenitor cells restricted to myeloid lineage and their leukemia counterparts. Neoplasma 2010;57(5):392-400. Go to original source... Go to PubMed...
  43. Heuser M, Sly LM, Argiropoulos B, Kuchenbauer F, Lai C, Weng A, Leung M, Lin G, Brookes C, Fung S, Valk PJ, Delwel R, Lowenberg B, Krystal G, Humphries RK. Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal. Blood 2009;114(19):3983-93. Go to original source... Go to PubMed...
  44. Gundogdu MS, Liu H, Metzdorf D, Hildebrand D, Aigner M, Aktories K, Heeg K, Kubatzky KF. The haematopoietic GTPase RhoH modulates IL3 signalling through regulation of STAT activity and IL3 receptor expression. Molecular Cancer 2010;9:225. Go to original source... Go to PubMed...
  45. Iwasaki T, Katsumi A, Kiyoi H, Tanizaki R, Ishikawa Y, Ozeki K, Kobayashi M, Abe A, Matsushita T, Wantabe T, Amano M, Kojima T, Kaibuchi K, Naoe T. Prognostic implication and biological roles of RhoH in acute myeloid leukaemia. Eur J Haematol 2008;81(6):454-60. Go to original source... Go to PubMed...
  46. Preti HA, Cabanillas F, Talpaz M, Tucker SL, Seymour JF, Kurzrock R. Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma. Ann Intern Med 1997;127(3):186-94. Go to original source... Go to PubMed...
  47. Fayad L, Keating MJ, Reuben JM, O'Brien S, Lee BN, Lerner S, Kurzrock R. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001;97(1):256-63. Go to original source... Go to PubMed...
  48. Dokter WH, Tuyt L, Sierdsema SJ, Esselink MT, Vellenga E. The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. Leukemia 1995;9(3):425-32. Go to PubMed...
  49. Schindler C, Darnell JE Jr. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem 1995;64:621-51. Go to original source... Go to PubMed...
  50. Kim H, Baumann H. Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. MolCell Biol 1999;19(8):5326-38. Go to original source... Go to PubMed...
  51. Nishida K, Yoshida Y, Itoh M, Fukada T, Ohtani T, Shirogane T, Atsumi T, Takahashi-Tezuka M, Ishihara K, Hibi M, Hirano T. Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. Blood 1999;93(6):1809-16. Go to original source...
  52. Chung TD, Yu JJ, Kong TA, Spiotto MT, Lin JM. Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. Prostate 2000;42(1):1-7. Go to original source... Go to PubMed...
  53. Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, Hibi M, Hirano T. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. EMBO J 1998;17(22):6670-7. Go to original source... Go to PubMed...
  54. Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse JF, Capiod JC, Delobel J, Weber-Nordt R, Dusanter-Fourt I, Dreyfus F, Groner B, Prin L. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 1996;87(5):1692-7. Go to original source... Go to PubMed...
  55. Schuringa JJ, Wierenga AT, Kruijer W, Vellenga E. Constitutive stat3, tyr705, and ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood 2000;95(12):3765-70. Go to original source...
  56. Tessier N, Hoang T. Transforming growth factor beta inhibits the proliferation of the blast cells of acute myeloblastic leukemia. Blood 1988;72(1):159-64. Go to original source...
  57. Batard P, Monier MN, Fortunel N, Ducos K, Sansilvestri-Morel P, Phan T, Hatzfeld A, Hatzfeld JA. TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation. J Cell Sci 2000;113:383-90. Go to original source... Go to PubMed...
  58. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998;67:753-91. Go to original source... Go to PubMed...
  59. Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell 1998;95(6):737-40. Go to original source... Go to PubMed...
  60. Wierenga ATJ, Schuringa JJ, Eggen BJL, Kruijer W, Vellenga E. Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-sz1 is mediated by caspase-dependent and -independent processes. Leukemia 2002;16(4):675-82. Go to original source... Go to PubMed...
  61. Mantovani A. The chemokine system: redundancy for robust outputs. Immunol Today 1999;20(6):254-7. Go to original source... Go to PubMed...
  62. Bendall L. Chemokines and their receptors in disease. Histol Histopathol 2005;20(3):907-26. Go to PubMed...
  63. Tanaka T, Bai Z, Srinoulprasert Y, Yang BG, Hayasaka H, Miyasaka M. Chemokines in tumor progression and metastasis. Cancer Sci 2005;96(6):317-22. Go to original source... Go to PubMed...
  64. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4(7):540-50. Go to original source... Go to PubMed...
  65. Rosenkilde MM, Schwartz TW. The chemokine system - a major regulator of angiogenesis in health and disease. APMIS 2004;112(7-8):481-95. Go to original source... Go to PubMed...
  66. Faaij CM, Willemze AJ, Revesz T, Balzarolo M, Tensen CP, Hoogeboom M, Vermeer MH, van Wering E, Zwaan CM, Kaspers GJ, Story C, van Halteren AG, Vossen JM, Egeler RM, van Tol MJ, Annels NE. Chemokine/chemokine receptor interactions in extramedullary leukemia of skin in childhood AML: differential roles for CCR2, CCR5, CXCR4 and CXCR7. Pediatr Blood Cancer 2010;55(2):344-8. Go to original source... Go to PubMed...
  67. Kittang AO, Hatfield K, Sand K, Reikvam H, Bruserud Ø. The chemokine network in acute myelogenous leukemia: molecular mechanisms involved in leukemogenesis and therapeutic implications. Curr Top Microbiol Immunol 2010;341:149-72. Go to original source... Go to PubMed...
  68. Hatfield KJ, Bedringsaas SL, Ryningen A, Gjertsen BT, Bruserud Ø. Hypoxia increases HIF-1α expression and constitutive cytokine release by primary human acute myeliod leukemia cells. European cytokine network 2010;21(3):154-64. Go to PubMed...
  69. Reikvam H, Hatfield KJ, Lassalle P, Kittang AO, Ersaver E, Bruserud Ø. Targeting the angiopoietin (Ang)/Tie-2 pathway in the crosstalk between acute myeloid leukemia and endothelial cells: studies of Tie-2 blocking antibodies, exogenous Ang-2 and inhibition of constitutive agonistic Ang-1 release. Expert Opin Investig Drugs 2010;19(2):169-83. Go to original source... Go to PubMed...
  70. Hatfield KJ, Reikvam H, Bruserud Ø. The crosstalk between the matrix metalloprotease system and the chemokine network in acute myeloid leukemia. Curr Med Chem 2010;17(36):4448-61. Go to original source... Go to PubMed...
  71. Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB. Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies. Cancer Res. 2005;65(24):11392-9. Go to original source... Go to PubMed...
  72. Tilton B, Ho L, Oberlin E, Loetscher P, Baleux F, Clark-Lewis I, Thelen M. Signal transduction by CXC chemokine receptor 4. Stromal cellderived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med. 2000;192(3):313-24. Go to original source... Go to PubMed...
  73. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13(22):2905-27. Go to original source... Go to PubMed...
  74. Nebreda AR, Gavin AC. Perspectives: signal transduction. Cell survival demands some Rsk. Science 1999;286(5443):1309-10. Go to original source... Go to PubMed...
  75. Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007;109(2):785-91. Go to original source... Go to PubMed...
  76. Konoplev S, Rassidakis GZ, Estey E, Kantarijan H, Liakou CI, Juany X, Andreeff M, Konopleva M, Medeiros LI. Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype. Cancer 2007;109(6):1152-6. Go to original source... Go to PubMed...
  77. Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004;104(2):550-7. Go to original source... Go to PubMed...
  78. Zheng F, Li H, Du W, Huang S. Role of hERG1 K(+) channels in leukemia cells as a positive regulator in SDF-1a-induced proliferation. Hematology 2011;16(3):177-84. Go to original source... Go to PubMed...
  79. Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K, Calandra G, DiPersio JF. Rapid mobilization of CD34_ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol 2004;22(6):1095-102. Go to original source... Go to PubMed...
  80. Flomenberg N, Devine SM, DiPersio JF, Liesveld J, McCarty JM, Rowley SD, Vesole DH, Badel K, Calandra G. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 2005;106(5):1867-74. Go to original source... Go to PubMed...
  81. Zeng Z, Samudio IJ, Munsell M, An J, Huang Z, Estey E, Andreeff M, Konopleva M. Inhibition of CXCR4 with the novel RCP 168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. Mol Cancor Ther 2006;5(12):3113-21. Go to original source... Go to PubMed...
  82. Zeng Z, Shi YX, Samudio IJ, Wang R, Ling X, Frolova O, Levis M, Rubin JB, Negrin RR, Estey EH, Konoplev S, Andreeff M, Konopleva M. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009;113(24):6215-24. Go to original source... Go to PubMed...
  83. Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999;10(4):463-71. Go to original source... Go to PubMed...
  84. Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA. Isoform-selective phosphoinositide 3´-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood 2009;113(22):5549-57. Go to original source... Go to PubMed...
  85. Reikvam H, Mosevoll KA, Melve GK, Gunther CC, Sjo M, Bentsen PT, Bruserud Ø. The Pretransplantation Serum Cytokine Profile in Allogenic Stem Cell Recipients Differs from Healthy Individuals, and Various Profiles are Associated with Different Risks of Posttransplantation Complications. Biology of Blood and Marrow Transplantation 2012;18(2):190-9. Go to original source... Go to PubMed...
  86. Ersaver E, Melve GK, Bruserud Ø. Future perspectives: should Th17 cells be considered as a possible therapeutic target in acute myeloid leukemia patients receiving allogenic stem cell transplantation? Cancer Immunol Immunother 2011;60:1669-81. Go to original source... Go to PubMed...
  87. Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, Rodolico G, Querci V, Abbate G, Angeli R, Berrino L, Fambrini M, Caproni M, Tonelli F, Lazzeri E, Parronchi P, Liotta F, Maggi E, Romagnani S, Annunziato F. Human interleukin 17-producing cells originate from a CD161+ CD4+ T cell precursor. J Exp Med 2008;205(8):1903-16. Go to original source... Go to PubMed...
  88. Valmori D, Raffin C, Raimbaud I, Ayyoub M. Human RORgammat+ TH17 cells preferentially differentiate from naive FOXP3+ Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci USA 2010;107(45):19402-7. Go to original source... Go to PubMed...
  89. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8(9):942-9. Go to original source... Go to PubMed...
  90. Santarlasci V, Maggi L, Capone M, Frosali F, Querci V, De Palma R, Liotta F, Cosmi L, Maggi E, Romagnani S, Annunziato F. TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol 2009;39(1):207-15. Go to original source... Go to PubMed...
  91. Bruserud Ø. Acute myelogenous leukemia blasts as accessory cells during T lymphocyte activation: possible implications for future therapeutic strategies. Leukemia 1999;13(8):1175-87. Go to original source... Go to PubMed...
  92. Bruserud Ø, Kittang AO. The chemokine system in experimental and clinical hematology. Curr Top Microbiol Immunol 2010;341:3-12. Go to original source... Go to PubMed...
  93. Ersvaer E, Liseth K, Skavland J, Gjertsen BT, Bruserud Ø. Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells. BMC Immunol 2010;11:38. Go to original source... Go to PubMed...
  94. Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, Qian J, Jin J, Xu H. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol 2009;158(2):199-204. Go to original source... Go to PubMed...
  95. Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A, Foon KA, Whiteside TL, Boyiadzis M. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res 2009;15(10):3325-32. Go to original source... Go to PubMed...
  96. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol 2011;29(5):487-94. Go to original source... Go to PubMed...
  97. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6(11):1133-41. Go to original source... Go to PubMed...
  98. Carvalho A, Cunha C, Di Ianni M, Pitzurra L, Aloisi T, Falzetti F, Carotti A, Bistoni F, Aversa F, Romani L. Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation. Bone Marrow Transplant 2010;45(11):1645-52. Go to original source... Go to PubMed...
  99. Liseth K, Sjo M, Paulsen K, Bruserud O, Ersvaer E. Early pre-engraftment, functional, in vitro responsiveness of T lymphocytes in allotransplanted, acute leukemia patients: proliferation and release of a broad profile of cytokines, possibly predictive of graft-versus-host disease. Eur Cytokine Netw 2010;21(1):40-9. Go to original source...
  100. Zhao XY, Xu LL, Lu SY, Huang XJ. IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 2011;41(2):514-26. Go to original source... Go to PubMed...
  101. Iclozan C, Yu Y, Liu C, Liang Y, Yi T, Anaseti C, Yu XZ. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transplant 2010;16(2):170-8. Go to original source... Go to PubMed...
  102. Yi T, ChenY, Wang L, Du G, Huang D, Zhao D, Johnston H, Young J, Todorov I, Umetsu DT, Chen L, Iwakura Y, Kandeel F, Forman S, Zeng D. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009;114(14):3101-12. Go to original source... Go to PubMed...
  103. Singh SP, Zhang HH, Foley JF, Hedrick MN, Farber JM. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J Immunol 2008;180(1):214-21. Go to original source... Go to PubMed...
  104. Lotem J, Sachs L. Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor and oncogenes. Leukemia 1996;10(6):925-31. Go to PubMed...
  105. Buyse M, Squifflet P, Lange BJ, Alonzo TA, Larson RA, Kolitz JE, George SL, Bloomfield CD, Castaigne S, Chevret S, Blaise D, Maraninchi D, Lucchesi KJ, Burzykowski T. Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia. Blood 2011;117(26):7007-13. Go to original source... Go to PubMed...
  106. Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, Hogge DE, Nilsson B, Or R, Romero AI, Rowe JM, Simonsson B, Spearing R, Stadtmauer EA, Szer J, Wallhult E, Hellstrand K. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood 2006;108(1):88-96. Go to original source... Go to PubMed...
  107. Buyse M, Squifflet P, Lucchesi KJ, Brune ML, Castaigne S, Rowe JM. Assessment of the consistency and of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia. Trials 2011;12:86. Go to original source... Go to PubMed...
  108. Firas AS, Demeckova E, Bojtarova E, Czako B, Hrubisko M, Mistrik M. Isolated extra-medullary relapse of acute leukemia following allogeneic bone marrow transplantation. Bratisl Lek Listy 2008;109(8):358-61. Go to PubMed...
  109. Kaushansky K. Signal transduction pathways. In: Kaushansky K, Lichmann MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT. Williams Hematology, Eighth Edition, McGraw-Hill, 2010. p. 183-9.
  110. Toffalini F, Demoulin J-B. New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood 2010;116(14):2429-37. Go to original source... Go to PubMed...
  111. Faderl S, Pal A, Bornmann W, Albitar M, Maxwell D, Van Q, Peng Z, Harris D, Liu Z, Hazan-Halevy I, Kantarjian HM, Estrov Z. Kit Inhibitor ApcK110 Induces Apoptosis and Inhibits Proliferation of Acute Myeloid Leukemia Cells. Cancer Res 2009;69(9):3910-7. Go to original source... Go to PubMed...
  112. Yang X, Liu L, Sternberg D, Tang L, Galinsky I, DeAngelo D, Stone R. The FLT3 Internal Tandem Duplication Mutation Prevents Apoptosis in Interleukin-3-Deprived BaF3 Cells Due to Protein Kinase A and Ribosomal S6 Kinase 1-Mediated BAD Phosphorylation at Serine 112. Cancer Res 2005;65(16):7338-47. Go to original source... Go to PubMed...
  113. Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfeld CD. Adverse prognostic significance of c-kit in adult acute myeloid leukemia with inv(16) and t(8,21): a Cancer and Leukemia Group B Study. J. Clin Oncol 2006;24(24):3904-11. Go to original source... Go to PubMed...
  114. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010;116(24):5089-102. Go to original source... Go to PubMed...
  115. Meyers CA, Albitar M, Estey E. Cognitive Impairment, Fatigue, and Cytokine Levels in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome. Cancer 2005;104(4):788-93. Go to original source... Go to PubMed...