Normal human thymocyte subsets required for T-ALL subgrouping
MedWire News: Dutch researchers have demonstrated that the use of normal human thymocyte subsets is essential for the correct interpretation of oncogenic activation and subgroup classification in T-cell acute lymphoblastic leukemia (T-ALL).
Ectopic oncogene expression is common to all T-ALLs, and the presence of oncogene transcripts, such as LMO2 (LIM domain only 2), LYL1 (lymphoblastic leukemia-derived sequence 1), TLX1 (T-cell leukemia homeobox 1), TLX3, TAL1 (T-cell acute lymphocytic leukemia 1), and NKX2-1 (NK2 homeobox 1), is regarded as a defining element of a T-ALL signature, explain Anton Langerak (Erasmus Medical Centre, Rotterdam, the Netherlands) and colleagues.
They add that subgroup classification based on oncogene expression often relies on comparisons made with incorrect biologic reference material, such as that from mice, which can result in misclassification of T-ALL subgroups.
"Although many have speculated and made assumptions regarding the usage of relevant reference material for T-ALL, no real attempt has been made to show that normal human thymocyte subsets are the most optimal biologically relevant reference material for comparison to T-ALL," write the researchers in the British Journal of Haematology.
To address this, Langerak and team evaluated expression of T-ALL oncogenes during normal human thymocyte development using realtime quantitative polymerase chain reaction.
They found that LMO2 and LYL1 were expressed in the most immature thymic stages and that expression gradually declined as cells moved up to the more mature pre-T-cell receptor (TCR)αβ stages. Traces of LMO2 and LYL1 transcripts were also detected in TCRγδ+ thymocytes.
No TAL1 transcripts were detected in any human thymic subset, a finding that is in contrast to the Tal1 expression observed in murine thymocytes, note the researchers.
Similarly, no transcripts of TLX1, TLX3 and NKX2-1 were detected in human thymocytes.
To investigate further, the researchers determined oncogene expression levels in samples taken from 39 patients with T-ALL, and compared the results with the normal human thymocyte maturation counterpart.
They observed that high LMO2 transcript levels in mature T-ALL subgroups were indicative of oncogenic activation, while LYL1 transcripts were mainly detected in the immature and TCRγδ+ T-ALL subgroups and were expressed at levels similar to those detected in their normal thymic counterparts.
These findings suggest that "LMO2 and LYL1 expression in immature and TCRγδ+ expressing T-ALL most likely reflects normal T-cell development rather than oncogenic activation. However, LMO2 or LYL1 expression in αβ-lineage T-ALL is truly oncogenic," the researchers remark.
"As TAL1, TLX1, TLX3 and NKX2-1 are not expressed during any of the thymic developmental stages, the presence of transcripts from these oncogenes in any T-ALL subgroup would be indicative of an abnormal transcriptional programme," they add.
Langerack and co-authors say that their findings highlight a discrepancy between the LMO2, LYL1, and TAL1 transcriptional program in human and mice thymocytes.
"This brings into question whether previous associations suggested between oncogene expression in human T-ALL and the transcriptional signature determined in murine thymocytes are accurate enough," they conclude.
By Laura Dean