A microRNA driver of B-cell leukaemia

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Published: 11 Jun 2016
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Prof Luigi Naldini - Universita Vita-Salute San Raffaele, Milan, Italy

Prof Naldini talks to ecancertv at EHA 2016 about a fragment of microRNA called miR-126, which has been found to regulate both haematopoietic stem cells (HSC) and B-cell acute lymphocytic leukaemia (B-ALL).

He describes results generated from a mouse model with doxycycline-repressible miR-126 expression that, when engrafted with human B-ALL blasts, undergoes induced disease recovery and relapse, depending on over or under expression.

Of these results, he notes that any modulation of miRNA-126 results in increased apoptosis and graft rejection in mice, confirming that human B-ALL depends on precise expression levels, and that imatinib treatment was less effective in miR-126 knockdown doses.

ecancer's filming at EHA 2016 has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

 

EHA 2016

A microRNA driver of B-cell leukaemia

Prof Luigi Naldini - Universita Vita-Salute San Raffaele, Milan, Italy


We have been investigating for several years some microRNAs associated or preferentially expressed in haematopoietic stem cell line progenitors, one of which is miR-126 which is highly expressed in the stem and progenitors cells and then is downregulated during differentiation. This microRNA controls or helps controlling the balance between proliferation and quiescence of stem cells so it’s one of the important factors which maintains the stem cell pool in normal cells. We have shown previously that if you change the expression of this microRNA by inhibiting or forcing its expression you change the stem cell capacity to proliferate or maintain.

Now obviously the important thing is this microRNA  is also associated with malignancies and we have found that if we force expression of this miR-126 in progenitors when normally it would be downregulated there is a high incidence of leukaemia development in mice both of a lymphoblastic and myeloblastic type.

When it comes to that downregulation, how does that make it more or less susceptible to certain therapies?

It may be an interesting target because of its opposing function at this point. We don’t have a targeting strategy yet, we have identified a potential target here. Because its role in haematopoietic stem cells is to maintain quiescence and prevent excess proliferation so if we inhibit this microRNA we may actually improve proliferation of normal stem cells. On the other hand, it has the opposite function in the leukaemia stem cells or in the ALL leukaemia cells so in that case if we inhibit that because we prevent the stem cell from being more quiescent in the leukaemia and more resistant to the chemotherapy we may actually make them sensitise more. So there is an opposing function which plays actually in this case to the therapy. If we inhibit that we potentially improve the state of normal stem cells and we actually make more fragile the leukemic stem cells. So it’s an interesting target for that reason.

This was experimented using doxycycline, is that right?

Yes, we had this expression of the microRNA controlled by doxycycline so essentially once leukaemia developed in the mice if we shut off expression of the miR-126 by doxy administration the leukemic cell crashed and actually the mice did recover, even if they were already highly severely symptomatic. So there was an addiction of the leukaemia to the continued expression of the miR-126.

When doxycycline was stopped was there any relapse or refractory rate?

We have seen some delayed relapse in some mice which escape at this point the control, as everyone has expected in this highly mutagenic setting. But the majority of mice did not relapse.

Is there anything else you would like to add to summarise this trial?

I would say that an important thing, of course, this is an experimental model in which we force expression of the microRNA in mouse stem cells but we have concurrently analysed samples from clinics of patients affected by lymphoblastic ALL and we have found that the miR-126 is highly expressed and again is an abnormal feature because you wouldn’t see that expression in the normal cell counterpart. The highest expression correlates also with the worst prognosis so this could be again an interesting target for potential pharmacological development.