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Medical Oncology

, Volume 27, Issue 3, pp 673–679 | Cite as

The role of heterogeneous nuclear ribonucleoprotein K in the progression of chronic myeloid leukemia

  • Qingfeng Du
  • Li Wang
  • Hongqian Zhu
  • Song Zhang
  • Lulu Xu
  • Weiyang Zheng
  • Xiaoli LiuEmail author
Original Paper

Abstract

Chronic myeloid leukemia (CML) is a neoplastic disease of the hematopoietic stem cell. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) may up-regulate the transcriptional activity of some oncogenes in cancerous cells. The aim of this study was to verify the expression pattern of hnRNPK in patients with CML, to explore its association with BCR-ABL and some abnormal signaling pathways, and to discover how hnRNPK contributes to the progression of CML. In this study, 15 patients with CML (9 in chronic phase and 6 in blast crisis) were enrolled in this study. The expression of hnRNPK in mononuclear cells (MNCs) from these patients was detected by Western blotting and fluorimeter-based quantitative real-time reverse transcriptase polymerase chain reaction. hnRNPK expression levels in K562 cell line and imatinib-resistant leukemic cell line K562R, following the treatments with the inhibitors of Ras-MAPK (PD98059), PI3K/AKT (LY294002), JAK/STAT (AG490) signaling pathways, and BCR-ABL [imatinib mesylate (IM)], were also determined. As the results, the overexpression of hnRNPK in protein and gene patterns was detected in MNCs from patients with CML comparing with normal donors. Especially, its level in MNCs from patients with CML-blast crisis was significantly higher than in CML-chronic phase cells (P < 0.01). After the treatment with PD98059 (at 4, 8, 24, and 48 h) and IM (at 48 h), the expression levels of hnRNPK in leukemic cell lines were decreased, comparing with DMSO control group (P < 0.05). In conclusion, the results suggest that the overexpression of hnRNPK, which is regulated by BCR-ABL and Ras-MAPK signaling pathways, may promote the progression of CML. hnRNPK would be a potential marker and therapeutic target of CML evolution.

Keywords

Chronic myeloid leukemia hnRNPK BCR-ABL Ras-MAPK Imatinib mesylate 

Notes

Acknowledgment

This study was supported by grants from the Key Programs of Science and Technology of Guangzhou City (No. 2006Z3-E0401) and the National Natural Science Foundation of China (No. 30271463).

References

  1. 1.
    Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103:4010–22.CrossRefPubMedGoogle Scholar
  2. 2.
    Druker BJ, Guilhot F, O’Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Barnes DJ, Palaiologou D, Panousopoulou E. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005;65:8912–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Modi H, McDonald T, Chu S. Role of BCR/ABL gene-expression levels in determining the phenotype and imatinib sensitivity of transformed human hematopoietic cells. Blood. 2007;109:5411–21.CrossRefPubMedGoogle Scholar
  5. 5.
    Radich JP. The biology of CML blast crisis. Hematology Am Soc Hematol Educ Program. 2007;2007:384–91.Google Scholar
  6. 6.
    Soverini S, Martinelli G, Rosti G. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23:4100–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Carpenter B, Mackay C, Alnabulsi A. The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression. Biochim Biophys Acta. 2006;1765:85–100.PubMedGoogle Scholar
  8. 8.
    Bomsztyk K, Denisenko O, Ostrowski J. HnRNP K: one protein multiple processes. Bioessays. 2004;26:629–38.CrossRefPubMedGoogle Scholar
  9. 9.
    Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A, et al. hnRNP A1 Nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol. 2002;22:2255–66.CrossRefPubMedGoogle Scholar
  10. 10.
    Danilo P, Bruno C. Translational regulation by the p210 BCR/ABL oncoprotein. Oncogene. 2004;23:3222–9.CrossRefGoogle Scholar
  11. 11.
    Moumen A, Masterson P, O’Connor MJ. HnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell. 2005;123:1065–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Ostareck-Lederer A, Ostareck DH, Cans C. c-src-Mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs. Mol Cell Biol. 2002;22:4535–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Ruan G-R, Qin Y-Z, Chen S-S, Li J-L, Ma X, Chang Y, et al. Abnormal expression of the programmed cell death 5 gene in acute and chronic myeloid leukemia. Leuk Res. 2006;30:1159–65.CrossRefPubMedGoogle Scholar
  14. 14.
    Pocaly M, Lagarde V, Etienne G, Ribeil J-A, Claverol S, Bonneu M, et al. Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia. Leukemia. 2007;21:93–101.CrossRefPubMedGoogle Scholar
  15. 15.
    Kichiro T, Jun YK, Eiji T. The Jab1/cop9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression. Blood. 2005;105:775–83.CrossRefGoogle Scholar
  16. 16.
    Ren R. Mechanism of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83.CrossRefPubMedGoogle Scholar
  17. 17.
    Wendel HG, Stanchina E, Cepero E. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. PNAS. 2006;103:7444–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Carpenter B, McKay M, Dundas SR. Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer. Br J Cancer. 2006;95:921–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Perrotti D, Cesi V, Trotta R. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet. 2002;30:48–58.CrossRefPubMedGoogle Scholar
  20. 20.
    Notari M, Neviani P, Santhanam R, Blaser BW, Chang J-S, Galietta A, et al. AMAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood. 2006;107:2507–16.CrossRefPubMedGoogle Scholar
  21. 21.
    McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Bäsecke J, et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia. 2008;22:708–22.CrossRefPubMedGoogle Scholar
  22. 22.
    Crews CM, Alessandrini A, Erikson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992;258:478–80.CrossRefPubMedGoogle Scholar
  23. 23.
    Alessi DR, Saito Y, Campbell DG, Cohen P, Sithanandam G, Rapp U, et al. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 1994;13:1610–9.PubMedGoogle Scholar
  24. 24.
    Rosen LB, Ginty DD, Weber MJ, Greenberg ME. Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron. 1994;12:1207–21.CrossRefPubMedGoogle Scholar
  25. 25.
    Cowley S, Paterson H, Kemp P, Marshall CJ. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994;77:841–52.CrossRefPubMedGoogle Scholar
  26. 26.
    Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H–1-benzopyran-4-one (LY294002). J Biol Chem. 1994;269:5241–8.PubMedGoogle Scholar
  27. 27.
    Meydan N, Grunberger T, Dadi H. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996;379:645–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Meshinchi S, Stirewalt DL, Alonzo TA, Zhang Q, Sweetser DA, Woods WG. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood. 2003;102:1474–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Milella M, Precupanu CM, Gregorj C, Ricciardi MR, Petrucci MT, Kornblau SM, et al. Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects. Curr Pharm Des. 2005;11:2779–95.CrossRefPubMedGoogle Scholar
  30. 30.
    Gambacorti-Passerini C, Barni R, Marchesi E, Verga M, Rossi M, Rossi F, et al. Sensitivity of the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of the disease. Br J Haematol. 2001;112:972–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Ye D, Wolff N, Li L. STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood. 2006;107:4917–25.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Qingfeng Du
    • 1
  • Li Wang
    • 2
  • Hongqian Zhu
    • 1
  • Song Zhang
    • 1
  • Lulu Xu
    • 1
  • Weiyang Zheng
    • 1
  • Xiaoli Liu
    • 1
    Email author
  1. 1.Department of Hematology, Nanfang HospitalSouthern Medical UniversityGuangzhouPeople’s Republic of China
  2. 2.Beijing Institute of BiotechnologyBeijingChina

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