AI Article Synopsis
- In acute promyelocytic leukemia (APL), the common fusion gene PML-RARα is typically linked to leukemia, but its effectiveness when expressed in mice is limited.
- Replacing the human PML fusion with a mouse version creates a more potent hybrid, murine PML-RARα (mPR), which is linked to a higher risk of leukemia.
- This mPR oncoprotein prevents cellular aging by inhibiting key cell-cycle regulators, pointing towards targeting senescence as a potential strategy for APL treatment.
Article Abstract
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 cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143011 | PMC |
| http://dx.doi.org/10.1073/pnas.1412944111 | DOI Listing |
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