Multiple mechanisms induce ectopic expression of LYL1 in subsets of T-ALL cell lines.
Basic helix-loop-helix (bHLH) transcription factors are essential for lymphocytic differentiation. Here, we have analyzed the complete bHLH family in T-cell acute lymphoblastic leukemia cell lines by expression profiling. Differential expression was detected for BHLHB2, HES1, HES4, HEY1, ID1, ID2, ID3, LYL1 and TAL1, highlighting dysregulation of family members with inhibitory activity. Subsequently we focused on the mechanisms responsible for aberrant expression of LYL1 in comparison to TAL1. Quantitative genomic PCR indicated microdeletions upstream of both, TAL1 and LYL1, targeting STIL/SIL and TRMT1, respectively. Additionally, one LYL1-expressing cell line exhibited amplification of TRMT1. While deletion of STIL correlated with expression of the STIL-TAL1 fusion transcript, no TRMT-LYL1 fusion transcripts were detected in parallel with genomic rearrangements thereof. Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors.
Nagel
Stefan
S
Dept of Human and Animal Cell Lines, DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr 7B, 38124 Braunschweig, Germany. sna@dsmz.de
Venturini
Letizia
L
Meyer
Corinna
C
Kaufmann
Maren
M
Scherr
Michaela
M
Drexler
Hans G
HG
MacLeod
Roderick A F
RA
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D009363:Neoplasm Proteins; C086541:LYL1 protein, human