Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

Molecular Cancer

Research

Martin J Firth¹  Alex H Beesley²  Amy L Samuels²  Janelle L Rampellini²  Jasmin YS Heng²  Jette Ford²  Ursula R Kees²  Misty-Lee Palmer³ 

[1] Division of Biostatistics and Genetic Epidemiology, Telethon Institute for Child Health Research, University of Western Australia Centre for Child Health Research, Perth, Australia;Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, University of Western Australia Centre for Child Health Research, Perth, Australia;Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, University of Western Australia Centre for Child Health Research, Perth, Australia;Curtin University of Technology School of Pharmacy, PerthWestern Australia;

关键词: Acute Lymphoblastic Leukemia;    Mixed Lineage Leukemia;    Mixed Lineage Leukemia Gene;    Mixed Lineage Leukemia Fusion;    Mixed Lineage Leukemia Fusion Protein;   

DOI  :  10.1186/1476-4598-9-284

 received in 2010-01-11, accepted in 2010-10-28,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundRearrangement of the mixed-lineage leukemia gene (MLL) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of MLL. In this study we have further explored the relationship between MLL status and GC sensitivity.ResultsNegative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL-rearrangements suggested that this relationship represented expression of wild-type MLL. Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis.ConclusionsThe data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.

【 授权许可】

Unknown   
© Beesley et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.