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

• Main Authors: Firth Martin J, Samuels Amy L, Heng Jasmin YS, Palmer Misty-Lee, Rampellini Janelle L, Beesley Alex H, Ford Jette, Kees Ursula R
• Format: Article
• Language: English
• Published: BMC 2010-10-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/9/1/284
• ISSN: 1476-4598

<p>Abstract</p> <p>Background</p> <p>Rearrangement of the mixed-lineage leukemia gene (<it>MLL</it>) 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 <it>MLL</it>. In this study we have further explored the relationship between <it>MLL </it>status and GC sensitivity.</p> <p>Results</p> <p>Negative correlation of <it>MLL </it>expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of <it>MLL</it>-rearrangements suggested that this relationship represented expression of wild-type <it>MLL</it>. Analysis of <it>MLL </it>expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. <it>In silico </it>analysis of published data demonstrated that reduced levels of <it>MLL </it>mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with <it>MLL</it>-rearranged ALL. RNAi knockdown of <it>MLL </it>expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type <it>MLL </it>in the control of cellular apoptosis.</p> <p>Conclusions</p> <p>The data suggests that reduced expression of wild-type <it>MLL </it>can contribute to GC resistance in ALL patients both with and without <it>MLL</it>-translocations.</p>