ESH AL 2018 | Understanding the evolution from haematopoietic stem cell to leukemic cell

The idea is essentially to really understand the structure of the haematopoietic blood system, and we’re interested more at the top of the hierarchy these haematopoietic stem cell that make up all the blood. And at the same time, because you know the abnormality could develop from the system where we are interested, also in leukemic development, and so we have actually at the similar level half of the lab working on the bad side leukaemia. And mostly leukemia for us has been the acute myeloid leukemia and we’ve started to do some work for the last few years in myeloid neoplasms like MDS, CMML, which is actually quite a continuum to the acute myeloid leukemia because some of these patients with MDS or CMML will actually transform into AML.

So we wanted to see also how you know what is the progression from a kind of benign chronic phase to an acute phase, and understand mechanistically and molecularly how it works. But during the last, I will say five years now, we have been really focusing on the interactions of either the normal order leukemic cells with the environment, which is the pulmo niche, as we call it, or the pulmo macro environment, and trying to identify players first. And I think we are clearly not the the leader on demonstrating that different population of stromal cells in the niche have specific role in regulating normal hematopoietic stem cells. Most of the work has been done in Mouse, and we don’t really know how human cells behave and what are the regulator’s, so we are trying our best to to find out whether what has been shown in mice is really similar in a human setting, and more important actually for the talk that I gave yesterday is the fact that in a male, we believe that a male is actually modulating the environment for their own purpose and their own growth, and these as instructive factors and that they crosstalk to the environment.

So we are trying to dissect that by looking at different sub-fraction of the stroma at the present time. We are really focusing lately on endothelial cells, and this came actually from a very simplistic view on trying to image the bone marrow of these immunodeficient mice. We saw actually by looking inside how the leukemia developed that they were very close related to the vasculature, so we further evaluated what was happening close to the vessel and we essentially find out that the AML that are developing in contact with endothelial cells are actually providing a better environment for the endothelial cells and that provoke an increase in nitric oxide. And this nitric oxide that is being secreted actually is pushing the endothelial cells to be more leaky, and because of the leakiness we believe that first, the chemotherapy are not as effective because the drugs don’t come at a high concentration in the vessel, but also this has another effect which means that the normal ways all stem cells are pushed out of the bone marrow, and they are in periphery and we see much more stem cell like cells mobilizing out.

And so the Leukemia essentially is winning the battle; they’re the only player in the niche I will say, and that’s one of the aspect of that and we actually saw that by inhibiting just this factor, and I’m sure there will be much other factors to discover, we actually could not only decrease the Leukemia by the fact that we’ve now seen to have been treatments of conventional chemotherapy in addition with an NOS inhibitor we essentially decrease the leakiness, actually stop the leakiness if you want, and have a better chemotherapy treatment on that. So of course you know it is still human leukemia into a mouse setting, so we we are aware that the PDX of the immunodeficient mice have some caveat, so we would like now to translate that to human human situations. And one way to do that is that we have an enabling project in clinics to see by MRI whether we confirm the leakiness of a vessel leakiness in patients of AML. That will be the first stage that we have to do, and if that is correct, we will try potentially some NOS inhibitors and quit treatment of certain patients in co-treatment with chemotherapy or not.

Maybe it’s early days to pass directly from an immunodeficient mice to clinical settings but that’s what we would like to pursue. But at the same time we are clearly aware that the thing that we see in a vessel is because we were able to visualize very easily the vessel structure under contact with the leukemia, but as mentioned the microenvironment is multifactorial; there’s tons of different stroma cells that have been shown important for the maintenance of normal stem cells so we would like now to dissect every component of the stroma in a systematic way, and hopefully not only just find a few markers or a few factors that may be important for mesenchymal stromal cells or osteoblastic cells but try to have a global view of how AML in general changed the environment in one way, because I think we are thinking about a crosstalk between one leukemia, I mean leukemia versus 100 endothelial cells, the mesenchymal cells and osteoblasts, but they also probably crosstalk between each other. So it’s a multifactorial things and we’d like to see if we can,  now that there’s some system biology system and computational modeling where we can integrate all this data that were generated into bigger pictures, try to make sense of how we can better target this leukemia. And I’m sure you know AML have different complexity, AML with different genetic or cytogenetic abnormalities, so one thing that at the present time we are looking simplistically at what are the major player that are similar in a number of different AML with different chromosomal abnormalities. And as I said genomic and abnormality, and after maybe we will have to meet more slowly by picking specific pattern for specific genetic abnormality because I think that will probably be every AML do the same thing to the stroma is going to be much complex I’m sure. But the present time already we have done some analysis by RNA-seq on the stroma, there’s at least some pathway that seems common between different AML with different completely  like for your NPM or complex karyotype. So the idea is that first go with the commonality and after we could potentially dissect what is very specific to space and or subtype.