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

• Published in: Molecular cancer Vol. 9; no. 1; p. 284
• Main Authors: Beesley, Alex H, Rampellini, Janelle L, Palmer, Misty-Lee, Heng, Jasmin Y S, Samuels, Amy L, Firth, Martin J, Ford, Jette, Kees, Ursula R
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28.10.2010; BioMed Central; BMC
• Subjects: Acute lymphocytic leukemia; Apoptosis; Cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Colleges & universities; Corticosteroids; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Experiments; Gene expression; Genes; Genetic aspects; Glucocorticoids - pharmacology; Health aspects; Humans; Lymphocytes - drug effects; Medical research; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Oligonucleotide Array Sequence Analysis; Pediatrics; Physiological aspects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; Australia
• DOI: 10.1186/1476-4598-9-284
• ISSN: 1476-4598

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. 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.