The long isoform of RUNX3 acts as a tumor supressor in human T-cell lymphoma

Runt-related transcription factor 3 (RUNX3) has been described as a tumor suppressor for gastric cancer and other solid malignancies. Despite its key role in physiological T-cell differentiation, there is rare information on its relevance for the development of human T-cell lymphoma or leukemia. Here we show that alterations of RUNX3 by either heterozygous deletion or methylation of its distal promoter can be observed in the tumor cells of 15/21 (71%) patients suffering from Sézary Syndrome (SS), an aggressive variant of cutaneous T-cell lymphoma. In consequence, mRNA levels of RUNX3/p46, the long isoform of RUNX3 – controlled by the proximal promoter – are significantly lower in SS tumor cells. Re-expression of RUNX3/p46 promotes apoptosis and slows down proliferation in a RUNX3/p46low cell line of cutaneous T-cell lymphoma. By this we present the first evidence that RUNX3 can act as a tumor suppressor in a human T-cell malignancy and suggest that this effect is predominantly mediated through the long isoform of this transcription factor, which has not been in the focus of previous studies. For the study The long isoform of RUNX3 acts as a tumor supressor in human T-cell lymphoma genomic aberrations of tumor material of 23 patients suffering from Sézary syndrome were analyzed using aCGH. 20 tumor samples are already included into the study GSE19000 and were re-evaluated with focus on chromosomal region 1p36. This data set is comprised of the 20 previous samples plus aCGH data of patients 21, 22 and 23.