GFI is crucial for AML1-ETO induced acute myeloid leukemia

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Published: 26 Jun 2012
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Dr Bert van der Reijden – Radboud University Nijmegen Medical Centre, Holland

Dr Bert van der Reijden talks to ecancer at the 17th European Haematology Association Congress in Amsterdam about onco-gene repression and de-repression.


AML1-ETO, transcription factors that affect gene expression in cancer cells, can potentially lead to identification of a drugable target during the transcription process.


During the study of AML1-ETO, GFI1 (growth factor independent 1) was also discovered. Dr van der Reijden’s study found that patients with the AML-ETO mutation have a high expression of GFI1.


The importance of this study is the identification of a crucial factor in the development of the leukaemia, which could result in drugs that inhibit the AML1-ETO and GFI1 expression, hopefully resulting in apoptosis of the cancer cells.


Filming supported by Amgen

17th Congress of EHA, Amsterdam, 14-17 June 2012


GFI is crucial for AML1-ETO induced acute myeloid leukaemia


Dr Bert van der Reijden – Radboud University Nijmegen Medical Centre, Holland



You’re looking at gene expression, oncogenes repression and de-repression is one of the things you’ve been talking about just now in the hall, and it may be possible to use some of these processes as a target for cancer treatment. Now can you tell me what you’ve been finding out about acute myeloid leukaemia and the AML1 and the ETO factors that you are talking about here?


Basically, we have studied the effects of the acute myeloid leukaemia 1 gene that is fused to the 821 gene in acute myeloid leukaemia.


That’s the ETO part?


That’s the ETO part indeed, yes, and these proteins function as transcription factors and, as a consequence of their fusion, gene expression programmes in cancer cells are deregulated. And we were interested in what is now a relevant target that is used by AML1 ETO to cause cancer.


And I know you’ve been looking at this in the lab, you’ve been using mice but what have you been doing?


Well what we’ve been doing is we’ve also been using primary cells from patients to look at what places AML1-ETO binds to the human genome, and by doing that we encountered a known oncogene and that oncogene is called growth factor independence 1.


So you’ve got growth factor independence 1, you’ve also got AML1-ETO. These are big players and they are helping you to understand the oncogenic process in AML?


Absolutely, yes.


What’s happening then?


So what we saw is that the patients that have this specific mutation, the AML1-ETO mutation, that exactly these patients have very high expression of the GFI1 oncogene and, having established that, we went back to mice models but also human leukaemia cell models, to show that the upregulation of this GFI1 oncogene is really relevant for the pathogenesis of the disease.


Now when you were talking about de-repression of gene repression, what is that all about?


Well some genes can activate expression of genes and other proteins can repress that, and if proteins influence each other’s function proteins that normally would repress genes could be inhibited in their function and that results in de-repression.


So you believe, as a result of this, that very sophisticated work, that GFI1, growth factor independence 1, can be inhibited possibly as a target for cancer?


That is something we are investigating right now.


So what should doctors be gleaning from this sort of knowledge?


Indeed the main point here is that we have identified really the crucial factor in the early phases of the development of leukaemia that are targeted by an oncogenic fusion protein and what is also shown is that once a tumour cell line has been established that inhibiting this gene results in apoptosis of these cells. So this means that it’s an anti-apoptotic factor and right now we have small molecules to inhibit the function of this protein and we use it in mouse models to see whether that has therapeutic benefit.


Acute myeloid leukaemia, though, comes in many varieties. Is this kind of understanding going to be clear enough; will it be a big step forward if you can crack it?


Well one thing is that this mutation that I am talking about is occurring in 10% of the patients with acute myeloid leukaemia but what I also showed in my presentation is that about 20-30% of the patients with acute myeloid leukaemia have high expression of the GFI1 oncoprotein. So if it’s therapeutic, beneficial, to inhibit GFI1 we expect that it’s also beneficial in the 20 or 30 other percentage of the patients.


And, perhaps more importantly, this general approach, is that a proof of principle, that you can investigate at this level and actually make progress in what is after all a very difficult disease?


Well if we think about, for instance, another oncoprotein that’s called EZA1 that is also being activated, similar approaches are now being employed to inhibit that specific protein to cure leukaemia.


So, to sum up, how much hope would you like to give out at the moment for the medical community in their ability to treat, improve treatments, in acute myeloid leukaemia?


Improve treatments? Based on these findings we are really, I am honest, at the earliest phases of understanding the molecular mechanisms. If we can show with the small molecules that we have now that they can inhibit tumour progression and they can result in regression of tumours we may start phase I clinical trials in the near future to show the therapeutic efficacy and also the toxicity of such a kind of treatment.


And what should practising doctors make of this sort of finding?


That they have to be patient in the first place but that we are really getting into the understanding of the molecular mechanisms causing cancer and really identifying therapeutic targets.


That’s wonderful Bert. Thank you very much for joining us on


OK, my pleasure.