Master pathways and targets in T cell acute lymphoblastic leukaemia

Prof Jean Soulier - Hôpital Saint Louis, Paris, France

I was presenting the work of my lab and this is research work on the chromosomal abnormality which is deletion of chromosome 6q. So it is known for a very long time, it has been described forty years ago, but because it’s a large chromosomal deletion the molecular targets were not identified to date. We have been doing huge genomic work to characterise the minimal region of deletion and we identified two genes that are recurrently deleted in all cases with this translocation. We understood how it worked in terms of mechanistics because these two genes are involved in ribosome messenger RNA [?? 0:44]. The fact that they are lost pushes the cell into a state which is to be more dependent on the glycolysis with respect to the mitochondrial respiration. The stem cells are more strong, are more prone to re-initiate the disease with that abnormality and we showed that by mouse model profiling and by doing xenograft transplantation in mice.

How can that gene be targeted?

The applications are potential and we can imagine using this pathway, to target this pathway, to modulate the balance between glycolysis and mitochondrial respiration in this cell. But this balance is very subtle so that won’t be very easy to be just a good targeting of these cells. So that might be not that easy, we have trials in preclinical models ongoing in mice. We established leukaemia in mice and the aim is to see whether or not we can treat the mice with that before going on to patients.

Another possibility would be to use this deletion as a vulnerability because when you delete a chromosome you lose half the copy of the genes. Some of the genes are not at all relevant for the disease but because there is only one copy there is less and then you can target these [?? 2:29] genes in a way to go for vulnerability of the cell. So this is something we’re studying at the moment.

Does this gene play a role in any other cancers?

Yes, this is the case. We haven’t showed that yet, it is not in our paper on these two genes, but actually when we looked at the databases this gene can be mutated in other cancers. It can be mutated in acute myeloid leukaemia in a different way, meaning that these genes are lost in acute lymphoblastic leukaemia, the leukaemia we study, but in other leukaemias, myeloid leukaemia, they can be gained. Because it’s a kind of balance so they are pro-oncogenic when they are expressed in some leukaemias and they are pro-oncogenic when they are under-expressed in other leukaemias. So we plan to study that.

Were there any other presentations that you would like to highlight from the session?

Yes, there were some other presentations in the session. The aim of this session was to make the link between the fundamental research and translational and treatment. There was a very interesting presentation from Jan Cools, University of Leuven, and he showed that… actually he identified with his team a pathway which is downstream from the NOTCH signal in acute lymphoblastic leukaemia of this T-cell type. We have inhibitors of NOTCH that should be very potent but that failed in clinical trials because they have too many toxicities, too much toxicity. What Jan identified is that one of the downstream proteins can be targeted and this protein is expressed only in the leukemic cell, meaning that when he targets this protein then only the leukemic cell will be targeted without toxicity. So he showed that in a preclinical model, meaning in animal, and it is really very promising for therapeutics. So all the clinicians that were there, all the physicians, heard that and they are very interested to go into clinical tests. The paper will be out in one week.
Then we heard a novel insight from João Barata in Lisbon and Pieter Van Vlierberghe in Ghent. Both of them studied the transduction signal in acute lymphoblastic leukaemia, T-cell type as well, depending on the interleukin-7 receptor. They showed that we can imagine how to target these cells. So it’s not yet in clinic but it should be in a few years, let’s say.

Anything you would like to add?

It’s not an easy task to transfer the research into clinic in acute lymphoblastic leukaemia. The panel discussion was really dedicated to that – how can we transfer all the knowledge we have in genomics. We really have a very comprehensive view of how it works, how the cell became tumoural and stayed tumoural, stayed aggressive, but the transfer into clinic is not that easy. So it was a kind of brainstorming how we could do that and we have to work more, we have to use more preclinical models. One of the problems is that these are rare patients so altogether we have to put the patients together, make homogenous treatments to be able to really evaluate what happens in those patients.

Then there was a presentation, not that session but another, from Jean-Pierre Bourquin in Zurich. What Jean-Pierre does is for older resistant patients for the protocol, those with resistant disease, to put the cell in media and see whether they grew when they are exposed to many drugs, a huge number of drugs, the drugs you couldn’t test in all patients, you couldn’t test all these drugs in all the patients. So expose the cell like an antibiogram but a [?? 7:00] and test which drug would be active on which cells and try to pick the good drug for the good disease.