To investigate the potential functional role of NLS-RARα in leukemogenesis, HL-60 and U937 cell lines were transfected with NLS-RARα lentivirus and negative control (LVNC).
The promyelocytic leukemia (PML)/retinoic acid receptor-alpha (RARα) onco-fusion protein that is generated from t(15;17) chromosome translocation is crucial for the leukemogenesis of acute promyelocytic leukemia (APL) and is well documented as a transcriptional repressor.
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.
Together, these results indicated that NLS-RARα may be a novel transcription factor that contributes to leukemogenesis by competitively binding RAREs as heterodimers with RXRα, just as PML-RARα does, thus repressing the gene transcription essential for myeloid differentiation.
AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis.
FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m<sup>6</sup>A levels in these mRNA transcripts.
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.
This work identifies the TP53 tumor suppressor as a novel target through which NPM1-RARA impacts leukemogenesis, and confirms the importance of impairment of TP53 in establishment of the APL phenotype.
These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.
In primary murine hematopoietic progenitors, PLZF-RARalpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis.
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.
Altered PU.1 function is possibly implicated in leukemogenesis, as PU.1 gene mutations were identified in some patients with acute myeloid leukemia (AML) and as several oncogenic products (AML1-ETO, promyelocytic leukemia-retinoic acid receptor alpha, FMS-like receptor tyrosine kinase 3 internal tandem duplication) are associated with PU.1 downregulation.
Taken together, these data provide evidence that the dimerization capacity and the formation of a functionally charged pocket are indispensable for the PLZF/RARalpha-induced leukemogenesis.
Overexpression of N-CoR induces the differentiation of APL-derived NB4 cells, suggesting that the low levels of N-CoR in the nucleus may contribute at least partly to PML-RARalpha-mediated 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).
Here we show that while the X-RARalpha fusion gene is crucial for leukemogenesis, the presence of RARalpha-X and the inactivation of X function are critical in modulating the onset as well as the phenotype of the leukemia.
As an initial step to study the role of PML/RARalpha in leukemogenesis, we attempted to express the fusion protein in hematopoietic cells through retrovirus-mediated gene transfer of the retroviral vector, pGPRCHT, which contains the PML/RARalpha cDNA.
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.
The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells.
These observations suggest that in APL, the t(15;17) translocation generates an RAR mutant that could contribute to leukemogenesis through interference with promyelocytic differentiation.