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

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Open access
Authors
Beesley, A.
Rampellini, J.
Palmer, Misty-Lee
Heng, J.
Samuels, A.
Firth, M.
Ford, J.
Kees, U.
Date
2010
Type
Journal Article

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Beesley, Alex H. and Rampellini, Janelle L. and Palmer, Misty-Lee and Heng, Jasmin Y.S. and Samuels, Amy L. and Firth, Martin J. and Ford, Jette and Kees, Ursula R. 2010. Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia. Molecular Cancer. 9 (284): pp. 1-13.
Source Title
Molecular Cancer
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School
School of Pharmacy
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This article is published under the Open Access publishing model and distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/ Please refer to the licence to obtain terms for any further reuse or distribution of this work.

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Abstract

Background: Rearrangement 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.Results: Negative 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 ofwild-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 thatreduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverseclinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell linessignificantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wildtypeMLL in the control of cellular apoptosis. Conclusions: The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.