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R. Hleihel et al.
upregulation actually precedes NPM-1c loss, which is sug- gestive of the existence of at least another pathway of P53 activation. Indeed we found that RA plays an essential role in growth arrest through Pin1 inhibition in both OCI- AML3 and primary patients’ blasts of NPM-1c AML cells only. Downstream of Pin1 inhibition, we identified the PML and P53 growth suppressors as its essential down- stream effectors.36,46 Analysis of pml-/- and P53-/- AML3 cells demonstrated that P53 is downstream of PML-triggered Pin1 or RA responses. Our discovery of the key role of PML downstream of RA-initiated Pin1 inhibition (Figure 5D) suggests that RA-initiated Pin1 inhibition would upregulate PML and promote PML nuclear body forma- tion, ultimately driving P53/senescence. These results sug- gest that in NPM-1c-driven AML, but not in NPM1-WT AML, impairment of PML nuclear body formation is involved in leukemic transformation and that RA-mediat- ed restoration of PML nuclear bodies contributes to the therapeutic effects.
In NPM-1c-positive AML, elucidation of the respective contributions of PML nuclear bodies and NPM-1c degra- dation in the in vivo response, notably in combination with conventional chemotherapy, requires further inves- tigations. Yet, the absence of an effect of RA on clono- genic activity of Pin1 downregulated AML cells favors an important role of Pin1 inhibition in biological response and not only early P53 activation (Figure 2D). This model has several feed-forward loops, all favoring anti-prolifera- tive responses: RA-induced PML stabilization should facilitate PML-dependent NPM-1c degradation and P53 activation will enhance PML expression. Our results unravel a parallelism with the APL model: both involve oncoproteins that downregulate basal P53 signaling. In both, therapy response involves degradation of the driv-
ing oncogene, PML nuclear body formation and P53 acti- vation.8 The co-existence of other major oncogenes (epi- genetic regulators, FLT3) in NPM-1c-positive AML most likely explains why RA/ATO is not curative on its own. Nevertheless, RA could favor the action of chemotherapy, possibly by reverting basal Pin1 activation and P53 inhibi- tion. Our observations could explain the clinical benefit of the co-administration of RA with conventional chemotherapy in NPM-1c-positive AML.13,16 More broad- ly, the RA/ATO combination could target malignancies in which Pin1 and/or PML are deregulated.26,27 In this respect, clinical responses by solid tumors were observed in some RA/ATO-treated APL patients who had another synchronous malignancy,47,48 possibly reflecting activation of the RA/Pin1/PML/P53 axis elucidated by this study.
Disclosures
No conflicts of interest to disclose.
Contributions
RH, HCW, and CB performed experiments; ZHH treated patients; RM collected bone marrow samples; RH, HEH, HCW, CB, ZC, MES, HdT, and AB. analyzed results; RH, HEH, HCW, and CB created the figures; HEH, AB, and HdT designed the research and wrote the paper.
Funding
This work was supported by the American University of Beirut (AUB) and the Lebanese National Council for Scientific Research (CNRSL) (Group Research Proposal GRP AUB-CNRSL) (to HEH and AB); the Paris laboratory is supported by INSERM, CNRS, College de France, Université de Paris, Ligue Contre le Cancer, TRANSCAN, CAMELIA, The Sjoberg Foundation, and Foundation St. Joseph.
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