Tumor Biology

, Volume 37, Issue 1, pp 217–225 | Cite as

Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia

  • Stefania Trino
  • Luciana De Luca
  • Vittorio Simeon
  • Ilaria Laurenzana
  • Annalisa Morano
  • Antonella Caivano
  • Francesco La Rocca
  • Giuseppe Pietrantuono
  • Gabriella Bianchino
  • Vitina Grieco
  • Elisabetta Signorino
  • Alberto Fragasso
  • Maria Teresa Bochicchio
  • Claudia Venturi
  • Gianantonio Rosti
  • Giovanni Martinelli
  • Luigi Del Vecchio
  • Daniela Cilloni
  • Pellegrino Musto
Original Article
  • 140 Downloads

Abstract

Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.

Keywords

Chronic myeloid leukemia BCR-ABL1 Bridging integrator 1 Rab interactor 1 AXL 

Notes

Acknowledgments

We are grateful to Prof. Maria Alessandra Santucci and Dr. Enrico Bracco for technical and scientific advice. This paper was supported by Italian Ministry of Health, Current Research Funds for IRCCS, CUP E66J12000230001. DC was funded by grants from the following: AIRC “5 per 1000” and AIL.

Conflicts of interest

None

References

  1. 1.
    Cilloni D, Saglio G. Molecular pathways. BCR-ABL Clin Cancer Res. 2012;18(4):930–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83.CrossRefPubMedGoogle Scholar
  4. 4.
    Bruennert D, Czibere A, Bruns I, Kronenwett R, Gattermann N, Haas R, et al. Early in vivo changes of the transcriptome in Philadelphia chromosome-positive CD34+ cells from patients with chronic myelogenous leukaemia following imatinib therapy. Leukemia. 2009;23(5):983–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Wechsler-Reya R, Sakamuro D, Zhang J, Duhadaway J, Prendergast GC. Structural analysis of the human BIN1 gene. Evidence for tissue-specific transcriptional regulation and alternate RNA splicing. J Biol Chem. 1997;272(50):31453–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJ, Evans PR, et al. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science. 2004;303(5657):495–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Habermann B. The BAR-domain family of proteins: a case of bending and binding? EMBO Rep. 2004;5(3):250–5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ge K, Minhas F, Duhadaway J, Mao NC, Wilson D, Buccafusca R, et al. Loss of heterozygosity and tumor suppressor activity of BIN1 in prostate carcinoma. Int J Cancer. 2000;86(2):155–61.CrossRefPubMedGoogle Scholar
  9. 9.
    Ge K, Duhadaway J, Sakamuro D, Wechsler-Reya R, Reynolds C, Prendergast GC. Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity. Int J Cancer. 2000;85(3):376–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Tanida S, Mizoshita T, Ozeki K, Tsukamoto H, Kamiya T, Kataoka H, et al. Mechanisms of cisplatin-induced apoptosis and of cisplatin sensitivity: potential of BIN1 to act as a potent predictor of cisplatin sensitivity in gastric cancer treatment. Int J Surg Oncol. 2012;2012:862879.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Pan K, Liang XT, Zhang HK, Zhao JJ, Wang DD, Li JJ, et al. Characterization of bridging integrator 1 (BIN1) as a potential tumor suppressor and prognostic marker in hepatocellular carcinoma. Mol Med. 2012;18:507–18.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Elliott K, Ge K, Du W, Prendergast GC. The c-Myc-interacting adaptor protein BIN1 activates a caspase-independent cell death program. Oncogene. 2000;19(41):4669–84.CrossRefPubMedGoogle Scholar
  13. 13.
    DuHadaway JB, Sakamuro D, Ewert DL, Prendergast GC. BIN1 mediates apoptosis by c-Myc in transformed primary cells. Cancer Res. 2001;61(7):3151–6.PubMedGoogle Scholar
  14. 14.
    Balaji K, Mooser C, Janson CM, Bliss JM, Hojjat H, Colicelli J. RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR. J Cell Sci. 2012;125(Pt 23):5887–96.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kajiho H, Saito K, Tsujita K, Kontani K, Araki Y, Kurosu H, et al. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J Cell Sci. 2003;116(Pt 20):4159–68.CrossRefPubMedGoogle Scholar
  16. 16.
    Hu H, Bliss JM, Wang Y, Colicelli J. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Curr Biol. 2005;15(9):815–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Tall GG, Barbieri MA, Stahl PD, Horazdovsky BF. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev Cell. 2001;1(1):73–82.CrossRefPubMedGoogle Scholar
  18. 18.
    O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, et al. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991;11(10):5016–31.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Axelrod H, Pienta KJ. Axl as a mediator of cellular growth and survival. Oncotarget. 2014;5(19):8818–52.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hafizi S, Dahlbäck B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006;17(4):295–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Hafizi S, Dahlbäck B. Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J. 2006;273(23):5231–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Dufies M, Jacquel A, Belhacene N, Robert G, Cluzeau T, Luciano F, et al. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells. Oncotarget. 2011;2(11):874–85.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013;122(14):2443–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011;10(10):1763–73.CrossRefPubMedGoogle Scholar
  25. 25.
    Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014;5(20):9546–63.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mahadevan D, Theiss N, Morales C, Stejskal AE, Cooke LS, Zhu M, et al. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2014.Google Scholar
  27. 27.
    Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26(10):2172–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Arruga F, Messa F, Pradotto M, Bernardoni R, Bracco E, Carturan S, et al. Disabled gene is involved in CML progression and its expression level at diagnosis can predict major molecular response (MMR) to imatinib therapy. Cancer Res (Annual Meeting of the American Association for Cancer Research Abstract). 2010;70(Suppl 1).Google Scholar
  29. 29.
    Cilloni D, Pradotto M, Messa F, Arruga F, Bracco E, Carturan S, et al. Identification of Rab5 as a gene involved in chronic myeloid leukemia (CML) progression. Blood (ASH Annual Meeting Abstracts). 2009;114:3470.Google Scholar
  30. 30.
    Abella JV, Park M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metabol. 2009;296(5):E973–84.CrossRefGoogle Scholar
  31. 31.
    de Jong R, ten Hoeve J, Heisterkamp N, Groffen J. Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. J Biol Chem. 1995;270(37):21468–71.CrossRefPubMedGoogle Scholar
  32. 32.
    Dinulescu DM, Wood LJ, Shen L, Loriaux M, Corless CL, Gross AW, et al. c-CBL is not required for leukemia induction by Bcr-Abl in mice. Oncogene. 2003;22(55):8852–60.CrossRefPubMedGoogle Scholar
  33. 33.
    Roepstorff K, Grovdal L, Grandal M, Lerdrup M, van Deurs B. Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer. Histochem Cell Biol. 2008;129(5):563–78.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Grosso S, Puissant A, Dufies M, Colosetti P, Jacquel A, Lebrigand K, et al. Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR-ABL inhibitors. Mol Cancer Ther. 2009;8(7):1924–33.CrossRefPubMedGoogle Scholar
  35. 35.
    Lu L, Saunders V, Kok CH, Leclercq T, Hughes TP, White DL. Modeling ponatinib resistance in BCR-ABL1+ cell lines: implications for Ponatinib resistance in TKI-resistant and TKI-naïve patients. Blood (ASH Annual Meeting Abstracts). 2014;124(21).Google Scholar
  36. 36.
    Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, et al. Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood. 2011;118(8):2211–21.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Stefania Trino
    • 1
  • Luciana De Luca
    • 1
  • Vittorio Simeon
    • 1
  • Ilaria Laurenzana
    • 1
  • Annalisa Morano
    • 1
  • Antonella Caivano
    • 1
  • Francesco La Rocca
    • 1
  • Giuseppe Pietrantuono
    • 2
  • Gabriella Bianchino
    • 3
  • Vitina Grieco
    • 3
  • Elisabetta Signorino
    • 4
  • Alberto Fragasso
    • 5
  • Maria Teresa Bochicchio
    • 6
  • Claudia Venturi
    • 6
  • Gianantonio Rosti
    • 6
  • Giovanni Martinelli
    • 6
  • Luigi Del Vecchio
    • 7
    • 8
  • Daniela Cilloni
    • 4
  • Pellegrino Musto
    • 9
  1. 1.Laboratory of Pre-clinical and Translational ResearchIRCCS Referral Cancer Center of BasilicataRionero in VultureItaly
  2. 2.Department of Onco-HematologyIRCCS Referral Cancer Center of BasilicataRionero in VultureItaly
  3. 3.Laboratory of Clinical Research and Advanced DiagnosticsIRCCS Referral Cancer Center of BasilicataRionero in VultureItaly
  4. 4.Department of Clinical and Biological SciencesUniversity of TurinTurinItaly
  5. 5.Hematology UnitOspedale Madonna delle Grazie, ASMMateraItaly
  6. 6.Institute of Hematology “L. e A. Seràgnoli”, Department of Experimental, Diagnostic and Specialty MedicineUniversity of BolognaBolognaItaly
  7. 7.Biotecnologie AvanzateCEINGENaplesItaly
  8. 8.Department of Molecular Medicine and Medical Biotechnologies“Federico II” University of NaplesNaplesItaly
  9. 9.Scientific DirectionIRCCS Referral Cancer Center of BasilicataRionero in VultureItaly

Personalised recommendations