Novel RUNX1 Isoforms Determine the Fate of Acute Myeloid Leukemia Cells by Controlling CD56 Expression.
Stefan Gattenlohner, Edgar Serfling, Hermann Einsele, Hans-Konrad Muller-Hermelink. Institute of Pathology, Medical University of Graz, Austria; Institute of Pathology, University of Würzburg, Germany; University of Würzburg, Germany
Background: In acute myeloid leukemias (AMLs), CD56(NCAM) expression occurs in 15-20% of cases and is an independent negative prognostic marker that is associated with a poor response to chemotherapy and with increased relapse rates, resulting in a shorter overall survival of affected patients. Furthermore, clonal evolution of leukemic blasts with CD56 expression has been observed in originally CD56(-) AMLs following on relapse. To date, however, it has been unclear what regulates CD56 expression on AML cells and how it is linked to the aggressive AML phenotype. Recently, we reported that the transcription factor RUNX1 (AML1) controls CD56 expression by activation/inhibition of the CD56 promoter. Since RUNX1 is also one of the most frequently mutated genes in AMLs, we hypothesised that RUNX1 might also regulate CD56 expression in AMLs thereby controlling functional features of AML cells with relevance to their malignant potential.
Design: cDNA library synthesis and screening, RT-PCR and western blot, promotor studies and cell transfection, siRNA assay.
Results: We show here that multiple isoforms of RUNX1 are expressed in AML cells, and that a characteristic pattern of expressed RUNX1 isoforms correlates with CD56 expression. Abnormal over-expression of the full length p48 isoform in AML cells stimulated CD56 transcription, whereas three previously unknown RUNX1 isoforms, p38a, p30 and p24, suppressed it to a variable extent. Moreover, siRNA directed against p48 RUNX1 suppressed CD56 expression and NF-kB activation. Together, these findings suggests that strategies aimed at the balance between individual RUNX1 isoforms and/or NF-kB signalling could inhibit the survival of CD56high AML cells, thus providing promising new targets for therapy of this high-risk group of leukemias.
Conclusions: Beyond the field of translational AML research, our results might help to explain the many recent reports that correlate CD56 over-expression with an aggressive clinical phenotype in a variety of non-myeloid malignancies, including multiple myeloma and several common solid tumors such as colon carcinoma renal cancer and melanoma. Finally, since the regulatory properties of the new RUNX1 splice variants extend beyond CD56 to other RUNX1 target genes, the results could be therapeutically relevant for RUNX1-related gene regulation in a broad spectrum of clinical settings including heart diseases, haematology and autoimmunity.
Monday, February 28, 2011 2:15 PM
Platform Session: Section B, Monday Afternoon