Abstract
PML/RARA is the oncoprotein driving acute promyelocytic leukemia (APL). It suppresses genes expression by recruitment of a number of transcriptional repressors, resulting in differentiation block and malignant transformation of hematopoietic cells. Here, we found that mice primary hematopoietic progenitor cells (HPCs), transduced by DNA-binding-defective PML/RARA mutants, were deficient in colony formation. Further experiments showed that DNA-binding-defective PML/RARA mutants could not repress the transcription of retinoic acid regulated genes. Intriguingly, there were no significant differences of the micro-speckled intracellular distribution between the mutants and wild-type PML/RARA. Some retinoic acid target genes regulated by PML/RARA are involved in not only differentiation block but also hematopoietic cell self-renewal. Altogether, our data demonstrate that direct DNA-binding is essential for PML/RARA to immortalize hematopoietic cells, while disruption of PML-nuclear body does not seem to be a prerequisite for hematopoietic cell transformation.
Highlights
Acute promyelocytic leukemia (APL) accounts for about 12– 15% of the incidents of acute myeloid leukemia
To completely abrogate the DNA binding through heterodimer formation with RXR, M883R, T886R mutations were introduced in PML/RARA C580G mutant (Figure 1A)
Note that cells transduced by different PML/RARA mutants expressed similar levels of fusion proteins and had comparable PML/RARA modification adducts (Figure 1C)
Summary
Acute promyelocytic leukemia (APL) accounts for about 12– 15% of the incidents of acute myeloid leukemia. The K160 sumoylation site of PML/RARA which allows the recruitment of a potent repressor DAXX is decisive for ex vivo cell immortalization/differentiation arrest and in vivo APL pathogenesis [10]. The presence of RXR, the RARA heterodimeric partner, extends the binding of PML/RARA to more widely spaced direct repeats than the normal RARA/RXR heterodimers and is pivotal to transformation ex vivo [11,12,13,14]. These distinct properties of the fusion protein cooperate to enforce transcriptional repression. The treatment with all trans retinoic acid (ATRA) induces complete remissions [15], at least in part through reactivation of PML/RARA-dependent transcription and ubiquitin-proteasome dependent degradation of PML/RARA fusion protein [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
