Document Detail

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia.
MedLine Citation:
PMID:  22282267     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-27
Journal Detail:
Title:  Leukemia     Volume:  26     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-06     Completed Date:  2012-08-07     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1255-65     Citation Subset:  IM    
Department of Pediatric Oncology/Hematology, Erasmus Medical Center / Sophia Children's Hospital, Zuid-Holland, The Netherlands.
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MeSH Terms
Apoptosis / 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
Infant, Newborn
Myeloid-Lymphoid Leukemia Protein / genetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy,  metabolism*,  mortality
Prednisolone / pharmacology*
Prednisone / pharmacology
Pyrimidines / pharmacology
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Survival Rate
src-Family Kinases / antagonists & inhibitors
Reg. No./Substance:
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 Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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