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

Leukemia. 2013 Apr;27(5):1063-71. doi: 10.1038/leu.2012.372. Epub 2012 Dec 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A2 / genetics
  • Annexin A2 / metabolism*
  • Annexin A2 / 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*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Prednisolone / pharmacology*
  • Quinazolines / pharmacology
  • RNA, Messenger / analysis
  • S100 Proteins / physiology
  • src-Family Kinases / physiology*


  • 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