title: 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: Department of Pediatric Oncology/Haematology, Erasmus Medical Center/Sophia Children's Hospital, Dr Molewaterplein 50, Rotterdam, The Netherlands.
authors: J A P
authors: JA
authors: Spijkers-Hagelstein
authors: S
authors: S
authors: Mimoso Pinhanços
authors: P
authors: P
authors: Schneider
authors: R
authors: R
authors: Pieters
authors: R W
authors: RW
authors: Stam
mesh_terms: D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D052117:Benzodioxoles / Q000494:pharmacology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D009418:S100 Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D052117:Benzodioxoles; D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D011239:Prednisolone; D011799:Quinazolines; D012333:RNA, Messenger; D009418:S100 Proteins; D019061:src-Family Kinases; D000099248:S100 Calcium Binding Protein A10; C497422:KMT2A protein, human; C515233:saracatinib