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


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.
Beesley
Alex H
AH
Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, University of Western Australia Centre for Child Health Research, Perth, Australia.
Rampellini
Janelle L
JL
Palmer
Misty-Lee
ML
Heng
Jasmin Y S
JY
Samuels
Amy L
AL
Firth
Martin J
MJ
Ford
Jette
J
Kees
Ursula R
UR
D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005938:Glucocorticoids; D051788:Myeloid-Lymphoid Leukemia Protein