EHA 2016
Activated JAK-STAT signaling co-operates with HOXA9 to drive leukaemia
Dr Charles De Bock - KU Leuven, Leuven, Belgium
I’m Dr Charles De Bock and I’m from the laboratory of Jan Cools at KU Leuven in Belgium. The primary research that we do is on the JAK-STAT signalling pathway in T-cell acute lymphoblastic leukaemia and really its role in driving that cancer. What we have found is that specific mutations in JAK3 act as key oncogenic drivers and one of the questions we’ve been asking is patients come with not just one mutation but multiple mutations and we have this hypothesis that co-occurring mutations that co-occur significantly together probably cooperate in driving the cancer. If we can figure out what oncogenes cooperate then we can ask the question how can we intervene in that cooperation to try and diminish that cancer as a therapeutic.
Could you talk us through the methods of your research?
In this case what we did is we first looked at clinical data and we asked again the question if we have a JAK3 mutation what often occurs with that. Then from the clinical data what we found is that those cancers which are HOXA positive have lesions which drive HOXA9 or HOXA clustered genes and in particular HOXA9 was pulled out, that those often significantly correlate with those which are JAK3 positive or mutant for JAK3. So the model that we used was first in vitro cell lines to try and recapitulate that cooperation. We found that those cells which expressed both JAK3 mutants and HOXA9 could really rapidly grow in vitro and when we had a mouse model these mice suddenly succumbed to a very strong AML unfortunately. So what we’re trying to do now is remodel the mouse so that we have a lymphoblastic leukaemia, which we have been successful in getting, so we have this nice acute lymphoblastic leukaemia driven very aggressively when we express JAK3 mutants and HOXA9.
I was reading through the abstract, you mentioned transforming the stem cells in vitro with targeted resequencing. Could you tell us more about that?
One of the first assays we do is trying to do a transformation assay, like are the genes that we’re studying able to transform cells to cytokine independent growth. And that means most stem cells need cytokines like a signal which makes them proliferate. What we’ve found is that with JAK3 and HOXA9 when we put them into stem cells and we culture them ex vivo usually a normal stem cell will just die. In this case JAK3 and HOXA9 they can make these cells grow in the absence of all cytokines which is a key indicator that this is a true bona fine cooperating oncogenic event. What was the other question?
The resequencing.
The resequencing. So the resequencing, we did targeted resequencing of 155 T-cell leukaemia patients and that is where we got the data that showed that JAK3 mutant patients often co-express and ectopically over-express HOXA9.
How could these results be brought forward to clinicians in practice?
At this stage it’s very preliminary for how we can translate this knowledge but what we’re trying to understand now is knowing that activating STAT signalling can co-operate with HOXA9 we’re trying to think of a way to therapeutically intervene at the clinical level. There are already a number of JAK inhibitors which are specific for JAK3 in particular like tofacitinib or a JAK1 and JAK3 inhibitor ruxolitinib. In our mouse model if we use that as a monotherapy we get an attenuated leukaemia, like repression, but not a consistent cure of these mice. So what we’re trying to do now is understand what are the additional pathways which are activated in the presence of HOXA9 and once we have that using these mouse models then we can say, OK, we want to use a JAK inhibitor with something else, be it a Wnt inhibitor or another inhibitor, which can then really have this combination targeted therapeutic strategy and try and move away from generic chemotherapy.
