Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood.
Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype.
However, the precise role of the APL-associated PML-RARα oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking.
Here, we report that cyclin-dependent kinase inhibitor 2C (CDKN2C) as a member of the cyclin-dependent kinase inhibitors is a target of the PML/RARα oncofusion protein in leukemogenesis of acute promyelocytic leukemia (APL).We found that CDKN2C was markedly downregulated in APL blasts compared with normal promyelocytes.
These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.
Here, like v-erbA, PML/RARa is a (strong) transcriptional repressor of the RA receptor (RAR) complex, and PML/RARa fusion receptor gene act as conditional oncogenic receptor (translocated chimeric retinoic acid a signaling) or oncogenic PML/RARa may participate in leukemogenesis of APL through blocking RA-mediated promyelocytic differentiation.This is first described in eukaryotes.
We discuss the roles of PML and PML-retinoic acid receptor alpha, as well as those of HIPK2 and p300 ubiquitination, in transcriptional regulation and leukemogenesis.
To identify genetic changes that cooperate with PML-RARA in leukemogenesis, we performed spectral karyotyping analysis of myeloid leukemias from hMRP8-PML-RARA mice (11 cases) and from mice coexpressing PML-RARA and BCL2 (8 cases).
According to this idea the PML-RARalpha fusion protein promotes leukemogenesis not only through repression of retinoic acid responsive genes, but also by way of interfering with several tumor suppressor proteins that cooperate to establish senescence.
In APL, the PML/RARalpha fusion interferes with both the retinoic acid (RA) response and PML localization on nuclear bodies, but the respective contribution of each defect to leukemogenesis is unclear.
Acute promyelocytic leukemia (APL) is characterized by the t(15;17) which involves the PML gene and the retinoic acid receptor alpha (RAR alpha) gene, and the subsequent PML/RAR alpha fusion gene is a key event in the leukemogenesis of APL.
Therefore, we hypothesized that disruption of the PML gene, a growth or transformation suppressor, by the t(15;17) translocation in APL is one of the critical events in leukemogenesis.
This observation, which highlights the importance of PML, is likely to be a key to unravelling the molecular mechanism of both leukemogenesis and RA-induced differentiation of APL.