The application of wildtype tumour-suppressor gene therapy on genetically variable osteosarcomas may be efficient only in yet not identified genetic subgroups of this tumour entity. Hyperactive tumour-suppressor transgenes could be an alternative.
In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19 ARF cell-cycle regulators. This induction coincides with a loss of the cancerassociated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.histone chaperones | leukemogenesis | hematopoiesis | oncogenes |
PML nuclear bodiesA cute promyelocytic leukemia (APL) is characterized by chromosomal translocations involving retinoic acid receptor alpha (RARα) with a limited number of translocation partners.
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