| Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. | |
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MedLine Citation:
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PMID: 22282267 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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J A P Spijkers-Hagelstein; P Schneider; E Hulleman; J de Boer; O Williams; R Pieters; R W Stam |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-01-27 |
Journal Detail:
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Title: Leukemia Volume: 26 ISSN: 1476-5551 ISO Abbreviation: Leukemia Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-06 Completed Date: 2012-08-07 Revised Date: 2013-03-04 |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: England |
Other Details:
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Languages: eng Pagination: 1255-65 Citation Subset: IM |
Affiliation:
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Department of Pediatric Oncology/Hematology, Erasmus Medical Center / Sophia Children's Hospital, Zuid-Holland, The Netherlands. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects Blotting, Western Calgranulin A / antagonists & inhibitors, genetics, metabolism* Calgranulin B / administration & dosage, genetics, metabolism* Drug Resistance, Neoplasm* Flow Cytometry Follow-Up Studies Gene Rearrangement* Glucocorticoids / pharmacology Humans Infant Infant, Newborn Myeloid-Lymphoid Leukemia Protein / genetics* Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy, metabolism*, mortality Prednisolone / pharmacology* Prednisone / pharmacology Prognosis Pyrimidines / pharmacology RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Survival Rate src-Family Kinases / antagonists & inhibitors |
| Chemical | |
Reg. No./Substance:
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0/AG 1879; 0/Calgranulin A; 0/Calgranulin B; 0/Glucocorticoids; 0/MLL protein, human; 0/Pyrimidines; 0/RNA, Messenger; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; 50-24-8/Prednisolone; 53-03-2/Prednisone; EC 2.7.10.2/src-Family Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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