Abstract HMGA2 is a major regulator of benign tumorigenesis from mesenchyme‐derived tissues and stem‐cell self‐renewal. It has been postulated that HMGA2 mediates its critical function by decreasing p16 Ink4a /p14 Arf expression and cellular senescence. To repress the oncogenic activity of HMGA2, the lin‐28‐let‐7 axis is thought to increasingly repress the expression of HMGA2 with age. To understand the HMGA2‐p14 Arf ‐relationship in benign tumorigenesis, we performed a series of experiments on mesenchymal stem‐cells, i.e., the proposed cells of origin of lipomas and uterine leiomyomas. The expression of both genes was inversely correlated during senescence in vitro but contrary to the expectations in adipose tissue derived stem cells (ADSCs) stimulation of HMGA2 by FGF1 increased the expression of p14 Arf . Based on the assumption that in ADSCs p14 Arf is repressing HMGA2, siRNA silencing of p14 Arf was performed resulting in a significant upregulation of HMGA2 . To see if p14 Arf can repress HMGA2 by a TP53‐dependent mechanism, nutlin‐3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta‐galactosidase, but also decreased the expression of HMGA2 , suggesting that p14 Arf indeed influences HMGA2 by a p53‐dependent mechanism because nutlin‐3 stabilizes p53. Accordingly, the HMGA2 response triggered by serum was reduced by treatment of ADSCs with nutlin‐3. As to the interaction between HMGA2 and p14 Arf in benign tumorigenesis, we propose a model where akin to MSC self‐renewal during tissue repair the simultaneous increase of p14 Arf with HMGA2 ensures genomic stability, whereas in turn p14 Arf can repress HMGA2 via TP53. © 2011 Wiley‐Liss, Inc.