ABSTRACT
The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease.
Subject(s)
Aldehyde Dehydrogenase/biosynthesis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase 1 Family , Cell Proliferation/physiology , Gene Expression Profiling , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Retinal Dehydrogenase , Signal TransductionABSTRACT
The connective tissue growth factor gene (CTGF) is aberrantly expressed in 75% of precursor B-cell acute lymphoblastic leukaemias (pre-B ALL) and is associated with poor outcome. We identified consistent hypomethylation of the CTGF locus in primary pre-B ALL specimens regardless of CTGF expression. By contrast, primary T-cell ALL specimens, which do not express CTGF, exhibited distinctive patterns of hypermethylation. Furthermore, we confirmed that global changes in DNA methylation and histone acetylation can both functionally modulate CTGF expression in pre-B ALL cell lines. These data suggest that hypomethylation of the CTGF locus is an essential prerequisite for aberrant CTGF expression in pre-B ALL.
Subject(s)
Connective Tissue Growth Factor/genetics , DNA Methylation , Gene Expression Regulation, Leukemic , Neoplasm Proteins/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Child , Connective Tissue Growth Factor/biosynthesis , CpG Islands , Decitabine , Humans , Hydroxamic Acids/pharmacology , Jurkat Cells/drug effects , Jurkat Cells/metabolism , Neoplasm Proteins/biosynthesis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Real-Time Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Glucocorticoids (GCs) are among the most important drugs for the treatment of acute lymphoblastic leukaemia (ALL). Cell lines cultured in high GC concentrations typically contain mutated glucocorticoid receptor (GR), something that is rarely found in primary ALL specimens. We studied naturally occurring mechanisms of GC resistance and examined sensitivity to GC in 15 T-ALL cell lines grown without prior exposure to drugs. Resistance could not be attributed to mutations in GR or variations in levels of its expression. We conclude that this panel of cell lines provides a suitable in vitro model since it reflects GC resistance in primary ALL.
