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

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.