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Acute Leukemias

Src kinase-induced phosphorylation of annexin A2 mediates glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

Leukemia volume 27, pages 1063–1071 (2013)Cite this article

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Abstract

MLL-rearranged infant acute lymphoblastic leukemia (ALL) (<1 year of age) are frequently resistant to glucocorticoids, like prednisone and dexamethasone. As poor glucocorticoid responses are strongly associated with therapy failure, overcoming glucocorticoid resistance may be a crucial step towards improving prognosis. Unfortunately, the mechanisms underlying glucocorticoid resistance in MLL-rearranged ALL largely remain obscure. We here defined a gene signature that accurately discriminates between prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL patient samples, demonstrating that, among other genes, high-level ANXA2 is associated with prednisolone resistance in this type of leukemia. Further investigation demonstrated that the underlying factor of this association was the presence of Src kinase-induced phosphorylation (activation) of annexin A2, a process requiring the adapter protein p11 (encoded by human S100A10). shRNA-mediated knockdown of either ANXA2, FYN, LCK or S100A10, all led to inhibition of annexin A2 phosphorylation and resulted in marked sensitization to prednisolone. Likewise, exposure of prednisolone-resistant MLL-rearranged ALL cells to different Src kinase inhibitors exerting high specificity towards FYN and/or LCK had similar effects. In conclusion, we here present a novel mechanism of prednisolone resistance in MLL-rearranged leukemias, and propose that inhibition of annexin A2 phosphorylation embodies a therapeutic strategy for overcoming resistance to glucocorticoids in this highly aggressive type of leukemia.

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Acknowledgements

We would like to express our gratitude to all the members and participating hospitals of the INTERFANT study groups for supporting our research by generously providing leukemic samples. Furthermore, we would gratefully thank Ingrid MAA Ariës, Monique L den Boer and Jules PP Meijerink (Pediatric Oncology, Erasmus Medical Center-Sophia’s Childrens Hospital) for providing gene-expression data of pediatric BCP-ALL and T-ALL patient samples.

Author contributions

JAPS-H designed and performed research and wrote the paper; SMP and PS performed research; RP designed and supervised research and reviewed the paper; RWS designed and supervised research and wrote the paper.

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Authors and Affiliations

  1. Department of Pediatric Oncology/Haematology, Erasmus Medical Center/Sophia Children’s Hospital, Rotterdam, The Netherlands

    J A P Spijkers-Hagelstein, S Mimoso Pinhanços, P Schneider, R Pieters & R W Stam

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  1. J A P Spijkers-Hagelstein
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Correspondence to R W Stam.

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Spijkers-Hagelstein, J., Mimoso Pinhanços, S., Schneider, P. et al. Src kinase-induced phosphorylation of annexin A2 mediates glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia 27, 1063–1071 (2013). https://doi.org/10.1038/leu.2012.372

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