Different p16INK4a and p14ARF expression patterns in acute myeloid leukaemia and normal blood leukocytes.

The p16INK4a gene is often disrupted or transcriptionally silenced by CpG island methylation in human cancers. However, in acute myeloid leukaemia (AML) alterations of the INK4a-ARF tumour suppressor locus are rarely found despite the noted variable p16INK4a mRNA and protein levels. The p14ARF, an alternative reading frame protein encoded from the same INK4a-ARF locus, is a potent tumour suppressor functionally linked to p53. There is little known regarding the role of p14ARF in primary human tumours. Therefore, we analysed the expression patterns of these two tumour suppressors in 37 cases of AML. The relative expression of p16INK4a and p14ARF mRNA in AML blasts, measured by a specific p16INK4a/p14ARF multiplex RT-PCR, was significantly shifted towards p14ARF whereas relatively lower levels of p16INK4a were detected. Quantitative RT-PCR revealed significantly higher expression of both transcripts in AML blasts when compared to normal differentiated myeloid cells or CD34+ progenitor cells. Furthermore, a good correlation between p16INK4a protein and mRNA was observed, whereas no correlation was found with p14ARF. Our results suggest: a) increased levels of both p16INK4a and p14ARF may participate in the pathogenesis of AML, b) that high p14ARF mRNA expression might influence p16INK4a transcription and c) that post-transcriptional regulatory mechanisms are important for p14ARF expression.