Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism.
Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.
Beesley
A 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, West Perth, Western Australia, PO Box 855, Australia 6872, Australia.
Firth
M J
MJ
Ford
J
J
Weller
R E
RE
Freitas
J R
JR
Perera
K U
KU
Kees
U R
UR
D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008775:Methylprednisolone / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D003907:Dexamethasone; D008775:Methylprednisolone