Abstract
It has been recently demonstrated that high pre‐treatment levels of miR‐29b positively correlated with the response of patients with acute myeloid leukaemia (AML) to hypomethylating agents. Upmodulation of miR‐29b by restoring its transcriptional machinery appears indeed a tool to improve therapeutic response in AML. In cells from acute promyelocytic leukaemia (APL), miR‐29b is regulated by PU.1, in turn upmodulated by agonists currently used to treat APL. We explored here the ability of PU.1 to also regulate miR‐29b in non‐APL cells, in order to identify agonists that, upmodulating PU.1 may be beneficial in hypomethylating agents‐based therapies. We found that PU.1 may regulate miR‐29b in the non‐APL Kasumi‐1 cells, showing the t(8;21) chromosomal rearrangement, which is prevalent in AML and correlated with a relatively low survival. We demonstrated that the PU.1‐mediated contribution of the 2 miR‐29b precursors is cell‐related and almost completely dependent on adequate levels of Vav1. Nuclear PU.1/Vav1 association accompanies the transcription of miR‐29b but, at variance with the APL‐derived NB4 cells, in which the protein is required for the association of PU.1 with both miRNA promoters, Vav1 is part of molecular complexes to the PU.1 consensus site in Kasumi‐1. Our results add new information on the transcriptional machinery that regulates miR‐29b expression in AML‐derived cells and may help in identifying drugs useful in upmodulation of this miRNA in pre‐treatment of patients with non‐APL leukaemia who can take advantage from hypomethylating agent‐based therapies.
Highlights
The use of hypomethylating agents has been found in recent years to correlate with a significant improvement in overall survival of patients with acute myeloid leukaemia (AML)
In acute promyelocytic leukaemia (APL)-derived cell treated with all-trans-retinoic acid (ATRA), Vav[1] is crucial for the interaction of PU.[1] with its DNA consensus regions on miR-142 promoter, the cooperation between the 2 proteins in modulating miR-29b expression was investigated in both APL- and non-APL–derived cells
As we previously found that, in APL-derived cells, Vav[1] regulates the presence of PU.[1] on its consensus region on the miR-142-3p promoter,[23] our subsequent aim was to assess whether, in regulation of miR-29b, the PU.[1] action is supported by Vav[1]
Summary
The use of hypomethylating agents has been found in recent years to correlate with a significant improvement in overall survival of patients with acute myeloid leukaemia (AML). Down-regulated in AML and whose restoration into AML cell lines or primary samples led to a dramatic reduction of tumorigenicity.[5,6,7] High pre-treatments levels of miR-29b have been recently associated with longer survival in AML patients treated with conventional chemotherapy and to improved clinical response to DNA methyltransferases (DNMT) inhibitors,[8,9] suggesting that strategies aimed to increase this miRNA may be useful in therapeutic DNA hypomethylation of leukaemic blasts. The ectopic expression of PU.[1] overcomes its functional block induced by AML1-ETO, in turn involved in a regulatory circuit with miR-29b1 that controls the leukaemic phenotype.[18,26] As we demonstrated that, in APL-derived cell treated with ATRA, Vav[1] is crucial for the interaction of PU.[1] with its DNA consensus regions on miR-142 promoter, the cooperation between the 2 proteins in modulating miR-29b expression was investigated in both APL- and non-APL–derived cells
Sign-in/Register to view highlights & summary 
Published Version (
Free)
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 call