T cell development and T cell leukaemia
Prof Hans-Reimer Rodewald - Universitätsklinikum Heidelberg, Heidelberg, Germany
I talked about the origin of acute T-cell leukaemia. I have been working on the thymus for many years and the thymus is the site of T-cell production and it’s normally dependent on progenitors entering from the bone marrow. These cells come in on a regular basis, probably daily, very few, and then they expand, they divide and they always then provide the current population of T-cell progenitors. What we discovered a few years ago is that if you cut off the supply of new progenitors going into the thymus then instead of what had been thought before, that the thymus would just run empty or be drained, then the cells in the thymus are not outcompeted anymore and they persist. So this is a phenomenon that we termed thymus autonomy, so it becomes autonomous for some time and independent of new progenitor supply from the bone marrow.
Interestingly, if you let this situation dwell for a while then the cells, these T-cell progenitors in the thymus, will transform and give rise to T-cell acute lymphoblastic leukaemia, or T-ALL. This is all done in mice and the T-ALLs that develop in this way have strong similarity to human T-ALL. So we think that there’s a possibility that a similar mechanism may operate also in humans because the true cause of the disease is not understood.
What are the therapeutic opportunities?
At the moment we don’t know because this pathway is very difficult to study. In humans and also in mice it’s not actually clear how you can identify these cells and whether or not they are provided on a regular basis, constantly, or whether this pathway can be interrupted. It’s conceivable that if you have a problem in the bone marrow, for example by a virus infection, that there will be a shortage of progenitors. So once the leukaemia is established the progenitor supply will not play a role anymore. So the underlying principle, what is called cell competition, so the whole idea of cell competition originally comes from work in the fly, in Drosophila, where you would have cells that compete, for example, for space or nutrients, and the compartment size is limited so it will not grow. So then cells can either win or lose, so you have winners or losers, and there has been this idea around for many years that this process can also be involved in cancer, either in the origin of cancer but also in the growth of cancer. For example under chemotherapy if you eliminate all the healthy cells you also eliminate the competition for the cancer cells so that’s actually a downside of the conventional therapy.
At the moment we don’t know whether in humans this can happen but there are reports that if you have a problem in the bone marrow, like anaplastic bone marrow or empty bone marrow, then you may recover from that and a few months later there are quite a few clinical reports that people have then developed acute lymphoblastic leukaemia. The link was completely unknown and for most of these reports these are B-ALLs but there are also reports for T-ALL. Of course the other disease that is reminiscent is myelodysplastic syndrome where you have also a problem to generate myeloid cells in the bone marrow which is very frequently then followed by transformation of the cells.
What are the next steps?
Today I talked about a genetic interrogation of this system. So there are typical mutations associated with this disease in humans and in mice in a gene called NOTCH. So these are activating mutations. We find them also in this model in the same sites, there are two hotspot clusters and we find them also there. The ones that are at the three prime end of the gene are usually so-called frameshift mutations where you have a change in the nucleotide sequence and that will lead to stop codon usage. We generated a new mouse model where we mutated all the potential stop codons to make it more difficult for the tumour and so this is an interesting allele because we then tested whether cells that bear one or two copies of this allele can still undergo transformation. The result is that they can still undergo transformation but then they overcome this hurdle by introducing a new type of mutation which are direct stop mutations. So there must be a huge pressure on this kind of mutation and also there must be a large number of mutations available for the tumours to select what is to their advantage.
Are these mutations also found in other types of cancer?
Yes, NOTCH mutations are also found in other types of cancers but they were really originally discovered in T-cell leukaemias and they are very prevalent in T-ALL in humans and in the mouse model that we use.
Anything you would like to add?
I’d like to add that I think this whole idea of cell competition as a condition, or disrupted cell competition, as a condition for transforming cells should be tested further in other systems. We are also trying that. Because the simple idea is that if you have a mutation in a cell that is gone tomorrow that’s not a problem. The problem only occurs if the cell persists.
So I think this whole idea that you first have a genetic hit and then the cell will undergo transformation, that could be true but you still need a cellular context that allows this. So that’s an idea that we are following up now.