The PML domain of PML–RARα blocks senescence to promote leukemia

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 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.

The short isoform of PML‐RARα activates the NRF2/HO‐1 pathway through a direct interaction with NRF2

“…NRF2 ∆ETGE was predominantly localized in the nucleus, and PR‐S showed weakly granular nuclear staining and clustered cytoplasmic staining (Fig. A), due to the absence of PML‐NLS, as described previously . Immunofluorescence staining revealed that PR‐S and NRF2 colocalized in the nucleus rather than the cytoplasm (Fig.…”

Classic and Variants APLs, as Viewed from a Therapy Response

“…At therapeutic concentrations, ATO induces the sumoylation of both PML-RARA and PML, leading to their proteasomal degradation in an RNF4-dependant manner [29][30][31]. PML-RARA degradation by arsenic derepresses expression of differentiation genes, as well as allows reformation of PML nuclear bodies and restoration of senescence [32][33][34][35]. In addition, ATO targeting of the normal PML allele enforces NB nuclear bodies (NB) formation and contributes to therapy response.…”

“…Even AML dedifferentiation may occur and explain clinical relapses [150]. Apart from differentiation, a mechanistically distinct consequence of therapy is loss of APL self-renewal [33][34][35]. Clinically, this is reflected by a decrease in the burden of leukemic cells, restoration of normal hematopoiesis and eradication of the APL clone driving long-term survival.…”

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

“…The immune system seems to be important for eliminating senescent cells involved in APL clearance [232,233]. Partner-mediated RARA dimerization is believed to be essential for arresting differentiation [234,235], and transformation requires the PML coiled-coil domain [236].…”