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  • Special Report
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New Abelson interactor-1 (Abi-1)-driven mechanism of acquired drug resistance

Leukemia Supplements volume 3, pages S7–S8 (2014)Cite this article

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The majority of chronic myeloid leukemia (CML) (actually all, according to WHO) and ~30% of acute lymphoblastic leukemia (ALL) cases in adults originate from transformation of a hematopoietic stem cell by the oncogenic kinase Bcr-Abl1.1 Despite the indisputable success of small-molecule inhibitors of Bcr-Abl1 in prolonging the survival of patients with Bcr-Abl1-positive leukemia, leukemic stem cells (LSCs) remain detectable in the bone marrow.2, 3, 4 There are two well-documented mechanisms of Bcr-Abl1-dependent resistance to tyrosine kinase inhibitor (TKI) treatment, both leading to cell autonomous activation of Bcr-Abl1 kinase: mutations in the catalytic domain and amplification of the oncogene.5, 6, 7 In addition, detailed mechanistic studies of imatinib mesylate (IM) resistance and persistence of Bcr-Abl1-containing hematopoietic stem cells (HSCs) have shown that primitive CML cells are capable of survival in the absence of Bcr-Abl1 kinase activity.2, 4, 8 These studies suggested the existence of a kinase activity-independent mechanism of acquired drug resistance. It is thought that primitive LSCs that are insensitive to the presence of TKI are responsible for relapse after TKI discontinuation. In this scenario, non-catalytic, adapter functions of Bcr-Abl1 are believed to contribute to the oncogenic characteristics of CML stem cells, indicating the necessity of identifying Bcr-Abl1 kinase-independent mechanisms of survival of LSCs in the presence of TKI.

Interactions of HSCs with the bone marrow microenvironment (BMME) are critical for sustaining stem cell pools.9 The stem cell niche regulates stem cell-specific properties, including self-renewal, multi-potentiality and relative quiescence.10 Evidence points to the involvement of the BMME in survival and systemic retention of LSCs.11, 12 Integrins, particularly α4β1 and αVβ3, which control trafficking to and lodging of HSCs in the BMME, are also crucial for the persistence of minimal residual disease.13, 14, 15 The Berlin–Frankfurt–Munster ALL trial (ALL-REZ BFM 2002) revealed that high expression of α4β1 at first relapse was associated with a poor molecular response to therapy and significantly worse event-free and overall survival.16 Based on these and other reports,17 a concept emerged suggesting that a subpopulation of LSCs are quiescent and exhibit relative drug resistance as a result of enhanced adhesive properties toward bone marrow stroma.18, 19 Abelson interactor 1 (Abi-1) was originally identified as Abl kinase associating protein 120 and was later confirmed to be one of the Bcr-Abl interactors.21 Recent reports indicate that the N-terminus of Abi-1 interacts with the cytoplasmic tail of α4 integrin, and may mediate specific functions associated with α4-dependent processes in normal and pathological conditions.22 Abi-1-deficient mice exhibit defects in placental and cardiovascular development leading to midgestational embryonic lethality;22, 23 these phenotypes mirror those found in mice deficient for α4 integrin or its ligand vascular cell adhesion molecule-1.24, 25 We have recently obtained evidence that Abi-1 plays a role in signaling cross talk between Bcr-Abl1 and α4 integrin. We have found that loss of Abi-1 leads to increased adhesion and quiescence, resulting in increased chemoresistance of leukemic CD34+ progenitor cells. An inverse correlation between Abi-1 and α4 integrin expression, as well as linkage of Abi-1 to elevated phospho-Akt and phospho-Erk signaling, was confirmed in IM-resistant leukemic cells. These results indicated that the α4-Abi-1 signaling pathway may mediate acquisition of the drug-resistant phenotype of leukemic cells.15 These results suggest that the α4 integrin–Abi-1–Bcr-Abl1 signaling module may play a significant role in interactions between LSCs and the BMME, and that alterations in this cross talk may be causative in the acquired drug-resistant phenotype of LSCs.

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References

  1. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW . Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 2012; 12: 513–526.

    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. Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 2012; 119: 1501–1510.

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. Lamontanara AJ, Gencer EB, Kuzyk O, Hantschel O . Mechanisms of resistance to BCR-ABL and other kinase inhibitors. Biochim Biophys Acta 2013; 1834: 1449–1459.

    Article  CAS  Google Scholar 

  8. Kavalerchik E, Goff D, Jamieson CH . Chronic myeloid leukemia stem cells. J Clin Oncol 2008; 26: 2911–2915.

    Article  Google Scholar 

  9. Morrison SJ, Scadden DT . The bone marrow niche for haematopoietic stem cells. Nature 2014; 505: 327–334.

    Article  CAS  Google Scholar 

  10. Kohli L, Passegue E . Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol 2014; 24: 479–487.

    Article  CAS  Google Scholar 

  11. Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med 2013; 19: 1513–1517.

    Article  CAS  Google Scholar 

  12. 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 

  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. Liu CC, Leclair P, Yap SQ, Lim CJ . The membrane-proximal KXGFFKR motif of alpha-integrin mediates chemoresistance. Mol Cell Biol 2013; 33: 4334–4345.

    Article  CAS  Google Scholar 

  15. Chorzalska A, Salloum I, Shafqat H, Khan S, Marjon P, Treaba D et al. Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia. Leukemia 2014; 28: 2165–2177.

    Article  CAS  Google Scholar 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

  25. Kwee L, Burns DK, Rumberger JM, Norton C, Wolitzky B, Terry R et al. Creation and characterization of E-selectin- and VCAM-1-deficient mice. Ciba Found Symp 1995; 189: 17–28(discussion 28-34, 77-18).

    CAS  Google Scholar 

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Acknowledgements

The symposium and publication of this supplement were sponsored by the Division of Hematology/Oncology at the Warren Alpert Medical School of Brown University and NIH Center of Biomedical Research Excellence (COBRE) for Stem Cells Biology at Rhode Island Hospital. We wish to acknowledge Rhode Island Foundation grant no. 20133980 (PMD).

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  1. Warren Alpert Medical School of Brown University, Signal Transduction Lab, Rhode Island Hospital, Providence, RI, USA

    A Chorzalska & P M Dubielecka

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Correspondence to P M Dubielecka.

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Chorzalska, A., Dubielecka, P. New Abelson interactor-1 (Abi-1)-driven mechanism of acquired drug resistance. Leukemia Suppl 3 (Suppl 1), S7–S8 (2014). https://doi.org/10.1038/leusup.2014.4

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