title: Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia.
abstract: MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca(2+) fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca(2+) and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca(2+) levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca(2+) fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center / Sophia Children's Hospital, Zuid-Holland, The Netherlands.
authors.forename: J A P
authors.initials: JA
authors.lastname: Spijkers-Hagelstein
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.forename: E
authors.initials: E
authors.lastname: Hulleman
authors.forename: J
authors.initials: J
authors.lastname: de Boer
authors.forename: O
authors.initials: O
authors.lastname: Williams
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: R W
authors.initials: RW
authors.lastname: Stam
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D040501:Calgranulin A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D005938:Glucocorticoids / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011239:Prednisolone / Q000494:pharmacology*; D011241:Prednisone / Q000494:pharmacology; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C412373:AG 1879; D040501:Calgranulin A; D040502:Calgranulin B; D005938:Glucocorticoids; C497422:KMT2A protein, human; D011743:Pyrimidines; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D011239:Prednisolone; D011495:Histone-Lysine N-Methyltransferase; D019061:src-Family Kinases; D011241:Prednisone