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Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia

Leukemia volume 28, pages 2165–2177 (2014)Cite this article

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Abstract

The basis for persistence of leukemic stem cells in the bone marrow microenvironment remains poorly understood. We present evidence that signaling cross-talk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in the acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl-positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl-positive CD34+progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate -resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug-resistant phenotype of leukemic cells.

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References

  1. Sloma I, Jiang X, Eaves AC, Eaves CJ . Insights into the stem cells of chronic myeloid leukemia. Leukemia 2010; 24: 1823–1833.

    Article  CAS  Google Scholar 

  2. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ . Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121: 396–409.

    Article  CAS  Google Scholar 

  3. Chomel JC, Bonnet ML, Sorel N, Bertrand A, Meunier MC, Fichelson S et al. Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 2011; 118: 3657–3660.

    Article  CAS  Google Scholar 

  4. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  Google Scholar 

  5. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res 2005; 65: 8912–8919.

    Article  CAS  Google Scholar 

  6. Keeshan K, Mills KI, Cotter TG, McKenna SL . Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype. Leukemia 2001; 15: 1823–1833.

    Article  CAS  Google Scholar 

  7. Hu Y, Chen Y, Douglas L, Li S . beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009; 23: 109–116.

    Article  CAS  Google Scholar 

  8. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 2007; 21: 926–935.

    Article  CAS  Google Scholar 

  9. Konig H, Holtz M, Modi H, Manley P, Holyoake TL, Forman SJ et al. Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. Leukemia 2008; 22: 748–755.

    Article  CAS  Google Scholar 

  10. Hoggatt J, Scadden DT . The stem cell niche: tissue physiology at a single cell level. J Clin Invest 2012; 122: 3029–3034.

    Article  CAS  Google Scholar 

  11. Park D, Sykes DB, Scadden DT . The hematopoietic stem cell niche. Front Biosci 2012; 17: 30–39.

    Article  CAS  Google Scholar 

  12. Lane SW, Scadden DT, Gilliland DG . The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood 2009; 114: 1150–1157.

    Article  CAS  Google Scholar 

  13. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9: 1158–1165.

    Article  CAS  Google Scholar 

  14. Mudry RE, Fortney JE, York T, Hall BM, Gibson LF . Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 2000; 96: 1926–1932.

    CAS  Google Scholar 

  15. Shalapour S, Hof J, Kirschner-Schwabe R, Bastian L, Eckert C, Prada J et al. High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse. Haematologica 2011; 96: 1627–1635.

    Article  CAS  Google Scholar 

  16. Nwajei F, Konopleva M . The bone marrow microenvironment as niche retreats for hematopoietic and leukemic stem cells. Adv Hematol 2013; 2013: 953982.

    Article  Google Scholar 

  17. Shi Y, Alin K, Goff SP . Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Genes Dev 1995; 9: 2583–2597.

    Article  CAS  Google Scholar 

  18. Brehme M, Hantschel O, Colinge J, Kaupe I, Planyavsky M, Kocher T et al. Charting the molecular network of the drug target Bcr-Abl. Proc Natl Acad Sci USA 2009; 106: 7414–7419.

    Article  CAS  Google Scholar 

  19. Scita G, Nordstrom J, Carbone R, Tenca P, Giardina G, Gutkind S et al. EPS8 and E3B1 transduce signals from Ras to Rac. Nature 1999; 401: 290–293.

    Article  CAS  Google Scholar 

  20. Scita G, Tenca P, Areces LB, Tocchetti A, Frittoli E, Giardina G et al. An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine. J Cell Biol 2001; 154: 1031–1044.

    Article  CAS  Google Scholar 

  21. Beli P, Mascheroni D, Xu D, Innocenti M . WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2. Nat Cell Biol 2008; 10: 849–857.

    Article  CAS  Google Scholar 

  22. Innocenti M, Gerboth S, Rottner K, Lai FP, Hertzog M, Stradal TE et al. Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nat Cell Biol 2005; 7: 969–976.

    Article  CAS  Google Scholar 

  23. Ryu JR, Echarri A, Li R, Pendergast AM . Regulation of cell-cell adhesion by Abi/Diaphanous complexes. Mol Cell Biol 2009; 29: 1735–1748.

    Article  CAS  Google Scholar 

  24. Innocenti M, Zucconi A, Disanza A, Frittoli E, Areces LB, Steffen A et al. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol 2004; 6: 319–327.

    Article  CAS  Google Scholar 

  25. Innocenti M, Frittoli E, Ponzanelli I, Falck JR, Brachmann SM, Di Fiore PP et al. Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1. J Cell Biol 2003; 160: 17–23.

    Article  CAS  Google Scholar 

  26. Sini P, Cannas A, Koleske AJ, Di Fiore PP, Scita G . Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nat Cell Biol 2004; 6: 268–274.

    Article  CAS  Google Scholar 

  27. Campa F, Machuy N, Klein A, Rudel T . A new interaction between Abi-1 and betaPIX involved in PDGF-activated actin cytoskeleton reorganisation. Cell Res 2006; 16: 759–770.

    Article  CAS  Google Scholar 

  28. Dubielecka PM, Machida K, Xiong X, Hossain S, Ogiue-Ikeda M, Carrera AC et al. Abi1/Hssh3bp1 pY213 links Abl kinase signaling to p85 regulatory subunit of PI-3 kinase in regulation of macropinocytosis in LNCaP cells. FEBS Lett 2010; 584: 3279–3286.

    Article  CAS  Google Scholar 

  29. Ring C, Ginsberg MH, Haling J, Pendergast AM . Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the alpha4 integrin. Proc Natl Acad Sci USA 2011; 108: 149–154.

    Article  CAS  Google Scholar 

  30. Dubielecka PM, Ladwein KI, Xiong X, Migeotte I, Chorzalska A, Anderson KV et al. Essential role for Abi1 in embryonic survival and WAVE2 complex integrity. Proc Natl Acad Sci USA 2011; 108: 7022–7027.

    Article  CAS  Google Scholar 

  31. Yang JT, Rayburn H, Hynes RO . Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 1995; 121: 549–560.

    CAS  Google Scholar 

  32. Kwee L, Baldwin HS, Shen HM, Stewart CL, Buck C, Buck CA et al. Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 1995; 121: 489–503.

    CAS  Google Scholar 

  33. La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ . Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 2002; 62: 7149–7153.

    CAS  Google Scholar 

  34. Yu C, Krystal G, Varticovksi L, McKinstry R, Rahmani M, Dent P et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res 2002; 62: 188–199.

    CAS  Google Scholar 

  35. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–1766.

    CAS  Google Scholar 

  36. Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 2013; 121: 1814–1818.

    Article  CAS  Google Scholar 

  37. Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW et al. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Genes Dev 1998; 12: 1415–1424.

    Article  CAS  Google Scholar 

  38. Konopleva MY, Jordan CT . Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol 2011; 29: 591–599.

    Article  Google Scholar 

  39. Puissant A, Dufies M, Fenouille N, Ben Sahra I, Jacquel A, Robert G et al. Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness. J Mol Cell Biol 2012; 4: 207–220.

    Article  CAS  Google Scholar 

  40. Rubio M, Nueda A, Vara A, Corbi Lopez AL . A single mRNA encodes the alpha 150 and alpha 80/70 forms of the alpha subunit of VLA4. Eur J Immunol 1992; 22: 1099–1102.

    Article  CAS  Google Scholar 

  41. Oostendorp RA, Dormer P . VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells. Leuk Lymphoma 1997; 24: 423–435.

    Article  CAS  Google Scholar 

  42. Qian H, Georges-Labouesse E, Nystrom A, Domogatskaya A, Tryggvason K, Jacobsen SE et al. Distinct roles of integrins alpha6 and alpha4 in homing of fetal liver hematopoietic stem and progenitor cells. Blood 2007; 110: 2399–2407.

    Article  CAS  Google Scholar 

  43. Garmy-Susini B, Jin H, Zhu Y, Sung RJ, Hwang R, Varner J . Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest 2005; 115: 1542–1551.

    Article  CAS  Google Scholar 

  44. Bonig H, Papayannopoulou T . Hematopoietic stem cell mobilization: updated conceptual renditions. Leukemia 2013; 27: 24–31.

    Article  CAS  Google Scholar 

  45. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007; 67: 684–694.

    CAS  PubMed Central  Google Scholar 

  46. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood 2013; 121: 1824–1838.

    Article  CAS  Google Scholar 

  47. Lo Celso C, Scadden DT . The haematopoietic stem cell niche at a glance. J Cell Sci 2011; 124 (Pt 21): 3529–3535.

    Article  CAS  Google Scholar 

  48. Stein AM, Bottino D, Modur V, Branford S, Kaeda J, Goldman JM et al. BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are reduced during imatinib treatment. Clin Cancer Res 2011; 17: 6812–6821.

    Article  CAS  Google Scholar 

  49. Jankowski W, Saleh T, Pai MT, Sriram G, Birge RB, Kalodimos CG . Domain organization differences explain Bcr-Abl's preference for CrkL over CrkII. Nat Chem Biol 2012; 8: 590–596.

    Article  CAS  Google Scholar 

  50. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P . Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 2010; 10: 858–870.

    Article  CAS  Google Scholar 

  51. Lewis BP, Burge CB, Bartel DP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Adam Lerner (Boston University), Dr Peter Quesenberry (Brown University), Dr T Papayannopoulou (University of Washington) and Dr Leszek Kotula (New York State University) for helpful discussions and Dr Tahereh Ziafazelli for technical assistance. We thank Dr Brian Druker and Dr Kara Johnson for providing us with the patient samples. This work received support from the National Center for Research Resources 5P20RR018757-10 and the National Institute of General Medical Sciences 8P20GM103414-10 (both to VF).

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Author notes

  1. A Chorzalska & P M Dubielecka

    Present address: 13Current address: Warren Alpert Medical School of Brown University, Signal Transduction Lab, Rhode Island Hospital, One Hoppin Street, Coro West, Suite 5.36, Providence, RI 02903, USA.,

Authors and Affiliations

  1. Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

    A Chorzalska, I Salloum, H Shafqat, S Khan, P Marjon & P M Dubielecka

  2. Hematopathology Laboratories at Rhode Island Hospital and Miriam Hospital, Providence, RI, USA

    D Treaba

  3. Genomics Core Facility, Brown University, Providence, RI, USA

    C Schorl

  4. Flow Cytometry and Cell Sorting Core Facility, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Providence, RI, USA

    J Morgan

  5. Cytogenetics, Quest Diagnostics Nichols Institute, Chantilly, VA, USA

    C R Bryke

  6. Department of Dermatology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

    V Falanga

  7. Departments of Dermatology and Biochemistry, Boston University School of Medicine, Boston, MA, USA

    V Falanga

  8. Department of Surgery, Cardiovascular Lab, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

    T C Zhao

  9. Division of Hematology/Oncology, Rhode Island Hospital, Brown University Warren Alpert School of Medicine, Providence, RI, USA

    J Reagan & E Winer

  10. Memorial Hospital of Rhode Island, Brown University Warren Alpert School of Medicine, Pawtucket, RI, USA

    A J Olszewski

  11. Adult Blood and Marrow Transplantation, Spectrum Health, Michigan State University, Grand Rapids, MI, USA

    A S Al-Homsi

  12. Department of Pathology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

    N Kouttab

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Chorzalska, A., Salloum, I., Shafqat, H. et al. Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia. Leukemia 28, 2165–2177 (2014). https://doi.org/10.1038/leu.2014.120

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