EHA 2016

RNA regulation of JAK-STAT pathways in CML

Prof Danilo Perrotti - The University of Maryland Baltimore, Baltimore, USA

MicroRNA are thought to be regulators of gene expression and they can do that in a canonical manner, like binding the three prime untranslated region of mRNA function or in a decoy manner and for decoy manner I mean it’s the ability of microRNA to bind proteins and prevent their function and we reported that in Cell in 2010. So we found out that there are other microRNAs which are capable of controlling multiple mRNAs at the same time and that also by modulating either in a canonical or in a decoy fashion. One of these is this miR300 which works in progenitor leukemic cells and in stem cells in two different manners. In leukemic, in the progenitor cell, its expression is not required for the pathogenesis of leukaemia. In fact, if you restore its expression like in normal cells you impair leukaemogenesis. In stem cells instead the levels of this microRNA are extremely high, like in normal cells, and we think that this microRNA is responsible for keeping the cells in their quiescent stage and therefore making the stem cell resistant to the current therapeutic drugs, tyrosine kinase inhibitors and so on.

Do you have any experimental data to support these ideas?

Yes, we do have experimental data, experimental both in vitro and in vivo, and there are also other experimenting in other currently ongoing in my lab.

Are there any results that you can share about these data?

Yes, there are. What we know in progenitor cells when we overexpress, when we restore the levels of this miR-300, it blocks the cell cycle and then what it does is targets a pathway which is a pathway that inhibits a tumour suppressor. This tumour suppressor is the main regulator of normal cell function, it’s called protein phosphatase 2A and the pathway which I’m talking about is the JAK2 set pathway. This is a pathway responsible for the regulation of cell survival or normal in leukemic cells.

Does this have any direct impact on CML therapy now or in the near future?

I do not think that targeting one single molecule is the solution for the eradication of a disease. I’m really quite sceptical about this single target molecule. Even BCR-ABL itself for CML which we thought was the cause of CML, indeed at the end is not the only one. So there are drugs which can reactivate these tumour suppressors, talking about PP2A, these drugs are called PAD, protein phosphatase 2A activating drugs, and they are capable of restoring the tumour suppressor activity and thereby totally killing the leukemic cells but not the normal in which the phosphatase activity of these tumour suppressors is extremely high.

Well that’s all the questions I have prepared, is there anything that you would like to add?

No, I hope to see more of these drugs which activate the tumour suppressor in the clinic soon.