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Integrins regulate survival of pre-B-ALL cells through differential IAP and caspase-7 ubiquitination and degradation

Leukemia volume 18, pages 873–875 (2004)Cite this article

TO THE EDITOR

The interactions between integrins and their ligands rescue normal and neoplastic B cells from apoptosis. In particular, adhesion-dependent cell survival has been observed for precursor B leukemia cells. Although cells isolated from most patients with pre-ALL undergo apoptosis when cultured in media alone, apoptosis is prevented in the presence of bone marrow stromal cells. Moreover, the prolongation of ALL cell survival is dependent on cell–cell contact signals between stromal and leukemic cells, with direct involvement of β1 integrins.1 Disruption of the adhesion with mAbs against α4β1 on the malignant cell or VCAM-1 on the stromal cell leads to apoptosis of the leukemia cells. Similarly, adhesion regulates survival of B-lineage leukemia cells during chemotherapy.2,3,4 Importantly, the integrin-dependent survival of leukemic cells in childhood ALL has been linked to the aggressiveness of the disease.5 It is therefore important to determine the mechanisms of integrin-mediated survival for potential clinical impact. Several mechanisms have been proposed. Integrins modulate bcl-2 family members in pre-B ALL cells.3 In AML cell lines, α4β1 integrin adhesion to fibronectin (Fn) leads to the activation of PI-3K/AKT with upregulation of bcl-2, which confers resistance to anoikis and drug resistance. Moreover, in a murine model, the combination of anti-VLA-4 antibodies and cytosine arabinoside conferred 100% survival, whereas chemotherapy alone had only a small impact.6 In pre-B ALL, we recently demonstrated that β1 integrin stimulation inhibited caspase-3 and -7 induction, and increased the expression of XIAP and Survivin, two inhibitors of apoptosis (IAP) family members.4 IAP proteins bind to and inhibit caspases. Most IAP proteins possess a Ring-finger motif at the C terminus, which confers an intrinsic ubiquitin ligase activity and promotes substrate-independent ubiquitination, upon apoptotic signals.7 On the other hand, IAP can also ubiquitinate several substrates, such as caspase-3 and -7, protecting the cells from apoptosis.8 Thus, apoptosis is controlled by a fine balance between the amounts of pro- and antiapoptotic molecules, regulated by degradation in the proteasome once ubiquitinated. In this study, we investigated the role of β1 integrins in the ubiquitination and degradation of these proteins.

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Acknowledgements

This work was supported by NIH grants CA81494, the Leukemia and Lymphoma Society, and the Norman Hirschfield Foundation. AA was partly supported by CNRS, France. We thank Dr Hamid Band (Boston, MA) for helpful discussion.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    A L Astier, M Svoboda, E Hinds, R de Beaumont, O Munoz & A S Freedman

  2. Department of Medicine, Harvard Medical School, Boston, USA

    A L Astier, M Svoboda, O Munoz & A S Freedman

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  1. A L Astier
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  2. M Svoboda
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Correspondence to A L Astier.

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Astier, A., Svoboda, M., Hinds, E. et al. Integrins regulate survival of pre-B-ALL cells through differential IAP and caspase-7 ubiquitination and degradation. Leukemia 18, 873–875 (2004). https://doi.org/10.1038/sj.leu.2403298

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