All Title Author
Keywords Abstract

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

DOI: 10.1186/1476-4598-9-284

Full-Text   Cite this paper   Add to My Lib


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 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.The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.Among pediatric subtypes of acute lymphoblastic leukemia (ALL), infants and those with T-lineage ALL are particularly resistant to glucocorticoids (GCs), one of the most important classes of drug for this disease [1]. Rearrangement of the mixed lineage leukemia gene (MLL) gene affects 80% of ALL in infants and is associated with a particularly poor prognosis [2,3]. MLL is located at 11q23 and encodes a histone methyltransferase that through its regulation of HOX genes is essential for normal mammalian development and hematopoiesis [4]. A unique feature of the MLL locus is that it is subject to an extremely wide variety of rearrangements, including translocations with >50 partner genes on various chromosomes, as well as deletions, inversions, internal duplications and gene amplifications [4-6]. There are conflicting reports on the relative GC responses of patients with different MLL translocations [7,8], but those with t(4;11) translocations appear particularly resistant [3,8,9]. The biological basis for the documented GC r


comments powered by Disqus