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

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.

• Authors: J A P Spijkers-Hagelstein, S Mimoso Pinhanços, P Schneider, R Pieters, R W Stam
• Journal: Leukemia (Leukemia) Vol. 27 Issue 5 Pg. 1063-71 (Apr 2013) ISSN: 1476-5551 [Electronic] England
• PMID: 23334362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A2
• Benzodioxoles
• KMT2A protein, human
• Quinazolines
• RNA, Messenger
• S100 Proteins
• S100 calcium binding protein A10
• Myeloid-Lymphoid Leukemia Protein
• saracatinib
• Prednisolone
• Histone-Lysine N-Methyltransferase
• src-Family Kinases

Topics

• Annexin A2 (genetics, metabolism, physiology)
• Benzodioxoles (pharmacology)
• Cell Proliferation
• Drug Resistance, Neoplasm
• Gene Rearrangement
• Histone-Lysine N-Methyltransferase
• Humans
• Myeloid-Lymphoid Leukemia Protein (genetics)
• Phosphorylation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Prednisolone (pharmacology)
• Quinazolines (pharmacology)
• RNA, Messenger (analysis)
• S100 Proteins (physiology)
• src-Family Kinases (physiology)