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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Although Acute Promyelocytic Leukemia (APL) has become a curable disease due to in-depth understanding of the underlying molecular processes, its investigation has provided unique and valuable insights into the processes involved in leukemogenesis. Therefore we use it as a model disease. 99% of APL-patients express a PML-RAR fusion protein. While involvement of RAR has proven indispensable for oncogenicity, the role of the PML domain is far less clear. In our previous study (Sternsdorf et al., Cancer Cell, 2006) we found that substitution of PML with heterologous self-interaction domains suffices to induce leukemias, but drastically decreases oncogenic potency of the resulting fusion proteins. In this study, we have chosen the inverse strategy: we have modified the PML domain to create a more active artificial model oncoprotein by adapting PR to its biological environment: As the typical model organism for APL studies is the mouse, we have replaced the human PML domain with the murine PML domain. This oncoprotein (mPR) creates APL-type leukemias in mice with higher penetrance and shorter latency than its human counterpart, hPR. We have used this system to study immediate early effects of expression of the model oncoprotein. While proliferating murine bone marrow cells go into senescence ex vivo, expression of mPR prevents this and robustly immortalizes murine bone marrow from every mouse strain tested so far. Senescence-associated upregulation of the cell-cycle regulators p21 and p19 was efficiently blocked by mPR expression. In mouse cells, mPR exhibits higher potency in disrupting the PML-associated Daxx/ATRX complex than hPR. Knockdown of ATRX, but not Daxx ameliorated ATRA-induced growth suppression and p21 upregulation in the human APL model cell line NB4. These data suggest, that PML-RAR promotes leukemogenesis by disrupting the Daxx/ATRX complex, which assembles at PML nuclear bodies during the onset of senescence. Disclosures: No relevant conflicts of interest to declare.

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