B-lymphoid transcriptional programme as a barrier against malignant transformation in acute lymphoblastic leukaemia
Prof Markus Müschen - City of Hope Comprehensive Cancer Center, Los Angeles, USA
My lab has been interested in normal B lymphocyte development and how this can go wrong towards the development of acute lymphoblastic leukaemia. A few years ago we made a surprising discovery that phosphatases, inhibitory molecules that are important in negatively regulating signal strength, are important for the survival of B-lymphoid leukaemias. That was very surprising to us because the current thinking in the field is that to make a tumour more aggressive it would need increase not decrease of signalling strength. So in our observation we found that these phosphatases are crucial to balance and to provide some equilibrium of oncogene signalling and that, much unlike what the field is proposing in other areas, that blocking the negative regulators can be a quite powerful way of preventing relapse and overcoming conventional mechanisms of drug resistance in leukaemia.
How are the lymphocytes normally regulated?
B-lymphocytes have to go through a number of developmental checkpoints during their development and the expression and the function of the so-called B-cell receptor plays a major role in this. This is also related to our main finding that these inhibitory phosphatases are crucial in these checkpoints. This is basically a quality control mechanism in which the functionality of B-cell receptors are being tested. Outcomes of this checkpoint could be that the receptor works just fine, it’s a strong persistent signal that drives proliferation and survival, but another outcome is that the receptor is not strong enough, in this case the cells fall below a minimum threshold of survival signals. Now what we’ve found is that it could also be the opposite – the signal is too strong – in which case the receptor is [?? 2:07] reactive and this also leads to negative selection and cell death. So this is the vulnerability in leukaemia that we identified and that we are now pursuing for therapeutic purposes.
Could personalised medicine play a role?
That’s a great question. The project that we are pursuing is fairly new, in fact probably we are, at City of Hope, the only group that is currently pursuing these therapeutic targets because they don’t fall in this mainstream category of signal inhibition. From that point of view it’s probably too early to say whether we can find individual patient specific vulnerabilities. What we can say, though, is that looking at different subtypes of leukaemia that they are not all the same, there are clearly differences in sensitivity. In our preclinical models we mostly work with mouse models in which we propagate patient derived cells. So when we divide those into different subtypes of leukaemia we find clear differences in responsiveness to the therapeutics.
What will these therapies target?
It’s basically feedback control of signal strength. So the observation was that normal B-cells but also B-cell lineage leukaemia cells need to maintain equilibrium or need to maintain balance. So the specific targets in this case are inhibitory phosphatases. Some of them are called PTEN or PTPN6 and DUSP6; they have all similar functions by negatively regulating kinases that they are opposing. So we have tested a number of small molecule inhibitors of these phosphatases and currently my lab is in the process of making a direct agonist or activator of a central tyrosine kinase called Syk which is the most proximal kinase in the B-cell receptor signalling pathway.
