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Chronic Myeloid Leukemia, BCR/ABL Studies and Myelo-Proliferative Syndromes

Identification of genes potentially involved in disease transformation of CML

Abstract

In patients with chronic myeloid leukemia (CML) who do not reach a (near) complete cytogenetic response, the disease progresses over several years from an indolent, chronic phase into a rapidly fatal blast crisis. Events that are responsible for this transformation process are largely unknown. To identify changes in gene expression that occurred during the course of the disease, we performed cDNA subtraction on sequentially stored peripheral blood mononuclear cell pellets, collected throughout the course of disease of a single CML patient. In total, 32 differentially expressed sequences were identified, of which 27 corresponded to known genes. On quantitative PCR, eight of these genes, YWHAZ, GAS2, IL8, IL6, PBEF1, CCL4, SAT and MMRN, showed comparable differential expression in additional CML patient samples. This set of genes can be considered as a starting point for further research on causes of disease transformation in CML and may lead to new targets in the treatment of resistant CML.

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References

  1. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042.

    Article  CAS  PubMed  Google Scholar 

  2. Bi S, Lanza F, Goldman JM . The involvement of ‘tumor suppressor’ p53 in normal and chronic myelogenous leukemia hemopoiesis. Cancer Res 1994; 54: 582–586.

    CAS  PubMed  Google Scholar 

  3. Yamaguchi H, Inokuchi K, Sakuma Y, Dan K . Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia. Leukemia 2001; 15: 1729–1734.

    Article  CAS  PubMed  Google Scholar 

  4. Griesshammer M, Heinze B, Bangerter M, Heimpel H, Fliedner TM . Karyotype abnormalities and their clinical significance in blast crisis of chronic myeloid leukemia. J Mol Med 1997; 75: 836–838.

    Article  CAS  PubMed  Google Scholar 

  5. Furukawa Y, DeCaprio JA, Belvin M, Griffin JD . Heterogeneous expression of the product of the retinoblastoma susceptibility gene in primary human leukemia cells. Oncogene 1991; 6: 1343–1346.

    CAS  PubMed  Google Scholar 

  6. Handa H, Hegde UP, Kotelnikov VM, Mundle SD, Dong LM, Burke P et al. Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase. Leuk Res 1997; 21: 479–489.

    Article  CAS  PubMed  Google Scholar 

  7. Shet AS, Jahagirdar BN, Verfaillie CM . Chronic myelogenous leukemia: mechanisms underlying disease progression. Leukemia 2002; 16: 1402–1411.

    Article  CAS  PubMed  Google Scholar 

  8. LeMaistre A, Lee MS, Talpaz M, Kantarjian HM, Freireich EJ, Deisseroth AB et al. Ras oncogene mutations are rare late stage events in chronic myelogenous leukemia. Blood 1989; 73: 889–891.

    CAS  PubMed  Google Scholar 

  9. Janssen JJWM, van Rijn RS, van der Holt B, Schuurhuis GJ, Vellenga E, Verhoef GE et al. Mobilisation of haemopoietic progenitors in CML: a second course of intensive chemotherapy does not improve Ph-negativity in stem cell harvests. Bone Marrow Transplant 2000; 25: 1147–1155.

    Article  CAS  PubMed  Google Scholar 

  10. de Kleijn DP, Smeets MB, Kemmeren PP, Lim SK, Van Middelaar BJ, Velema E et al. Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring. FASEB J 2002; 16: 1123–1125.

    Article  CAS  PubMed  Google Scholar 

  11. Giegerich R, Meyer F, Schleiermacher C . GeneFisher – software support for the detection of postulated genes. Proc Int Conf Intell Syst Mol Biol 1996; 4: 68–77.

    CAS  PubMed  Google Scholar 

  12. Stevens RL, Avraham S, Gartner MC, Bruns GA, Austen KF, Weis JH . Isolation and characterization of a cDNA that encodes the peptide core of the secretory granule proteoglycan of human promyelocytic leukemia HL-60 cells. J Biol Chem 1988; 263: 7287–7291.

    CAS  PubMed  Google Scholar 

  13. Le Y, Murphy PM, Wang JM . Formyl-peptide receptors revisited. Trends Immunol 2002; 23: 541–548.

    Article  CAS  PubMed  Google Scholar 

  14. Passey RJ, Xu K, Hume DA, Geczy CL . S100A8: emerging functions and regulation. J Leukoc Biol 1999; 66: 549–556.

    Article  CAS  PubMed  Google Scholar 

  15. Bullard JM, Cai YC, Spremulli LL . Expression and characterization of the human mitochondrial leucyl-tRNA synthetase. Biochim Biophys Acta 2000; 1490: 245–258.

    Article  CAS  PubMed  Google Scholar 

  16. Gordon MY, Dazzi F, Marley SB, Lewis JL, Nguyen D, Grand FH et al. Cell biology of CML cells. Leukemia 1999; 13 (Suppl. 1): S65–S71.

    Article  PubMed  Google Scholar 

  17. Johansson B, Fioretos T, Mitelman F . Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002; 107: 76–94.

    Article  CAS  PubMed  Google Scholar 

  18. Hermeking H . The 14-3-3 cancer connection. Nat Rev Cancer 2003; 3: 931–943.

    Article  CAS  PubMed  Google Scholar 

  19. Reuther GW, Fu H, Cripe LD, Collier RJ, Pendergast AM . Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14-3-3 family. Science 1994; 266: 129–133.

    Article  CAS  PubMed  Google Scholar 

  20. Sgorbissa A, Benetti R, Marzinotto S, Schneider C, Brancolini C . Caspase-3 and caspase-7 but not caspase-6 cleave Gas2 in vitro: implications for microfilament reorganization during apoptosis. J Cell Sci 1999; 112 (Part 23): 4475–4482.

    CAS  PubMed  Google Scholar 

  21. Benetti R, Del Sal G, Monte M, Paroni G, Brancolini C, Schneider C . The death substrate Gas2 binds m-calpain and increases susceptibility to p53-dependent apoptosis. EMBO J 2001; 20: 2702–2714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xie K . Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 2001; 12: 375–391.

    Article  CAS  PubMed  Google Scholar 

  23. Wierda WG, Johnson MM, Do KA, Manshouri T, Dey A, O'Brien S et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. Br J Haematol 2003; 120: 452–456.

    Article  PubMed  Google Scholar 

  24. Chiaretti S, Li X, Gentleman R, Vitale A, Vignetti M, Mandelli F et al. Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. Blood 2004; 103: 2771–2778.

    Article  CAS  PubMed  Google Scholar 

  25. Anand M, Chodda SK, Parikh PM, Nadkarni JS . Abnormal levels of proinflammatory cytokines in serum and monocyte cultures from patients with chronic myeloid leukemia in different stages, and their role in prognosis. Hematol Oncol 1998; 16: 143–154.

    Article  CAS  PubMed  Google Scholar 

  26. 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: 3765–3770.

    CAS  PubMed  Google Scholar 

  27. Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K et al. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. EMBO J 1998; 17: 6670–6677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I . Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 1994; 14: 1431–1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hufton SE, Moerkerk PT, Brandwijk R, de Bruine AP, Arends JW, Hoogenboom HR . A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization. FEBS Lett 1999; 463: 77–82.

    Article  CAS  PubMed  Google Scholar 

  30. Eaves CJ, Cashman JD, Wolpe SD, Eaves AC . Unresponsiveness of primitive chronic myeloid leukemia cells to macrophage inflammatory protein 1 alpha, an inhibitor of primitive normal hematopoietic cells. Proc Natl Acad Sci USA 1993; 90: 12015–12019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Taub DD, Ortaldo JR, Turcovski-Corrales SM, Key ML, Longo DL, Murphy WJ . Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. J Leukoc Biol 1996; 59: 81–89.

    Article  CAS  PubMed  Google Scholar 

  32. Chen Y, Kramer DL, Jell J, Vujcic S, Porter CW . Small interfering RNA suppression of polyamine analog-induced spermidine/spermine n1-acetyltransferase. Mol Pharmacol 2003; 64: 1153–1159.

    Article  CAS  PubMed  Google Scholar 

  33. Hayward CP, Kelton JG . Multimerin. Curr Opin Hematol 1995; 2: 339–344.

    Article  CAS  PubMed  Google Scholar 

  34. Hayward CP, Bainton DF, Smith JW, Horsewood P, Stead RH, Podor TJ et al. Multimerin is found in the alpha-granules of resting platelets and is synthesized by a megakaryocytic cell line. J Clin Invest 1993; 91: 2630–2639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ohmine K, Ota J, Ueda M, Ueno S, Yoshida K, Yamashita Y et al. Characterization of stage progression in chronic myeloid leukemia by DNA microarray with purified hematopoietic stem cells. Oncogene 2001; 20: 8249–8257.

    Article  CAS  PubMed  Google Scholar 

  36. Watari K, Tojo A, Nagamura-Inoue T, Nagamura F, Takeshita A, Fukushima T et al. Identification of a melanoma antigen, PRAME, as a BCR/ABL-inducible gene. FEBS Lett 2000; 466: 367–371.

    Article  CAS  PubMed  Google Scholar 

  37. Aman MJ, Rudolf G, Goldschmitt J, Aulitzky WE, Lam C, Huber C et al. Type-I interferons are potent inhibitors of interleukin-8 production in hematopoietic and bone marrow stromal cells. Blood 1993; 82: 2371–2378.

    CAS  PubMed  Google Scholar 

  38. Saleh AW, Hillen HF, Duits AJ . Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol 1999; 102: 31–37.

    Article  CAS  PubMed  Google Scholar 

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Janssen, J., Klaver, S., Waisfisz, Q. et al. Identification of genes potentially involved in disease transformation of CML. Leukemia 19, 998–1004 (2005). https://doi.org/10.1038/sj.leu.2403735

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