Chemo-genomic interrogation reveals JAK sensitive subgroup in AML

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Published: 12 Jun 2016
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Dr Vincent-Philippe Lavallée - Université de Montréal, Montréal, Canada

Dr Lavallée talks to ecancertv at EHA 2016 about a subtype of patients with acute myeloid leukaemia expressing CEBPA mutations.

He explains the further screening this subgroup through genomic and chemical screening to identify a cohort who express CSF3R mutations, which are sensitive to JAK inhibitors.

Dr Lavallée details these genes' frequency and overall genomic environment, how sensitivity to JAK inhibitors could inform treatment development and selection, as well as the overall importance of incorporating transcriptome data into research

ecancer's filming at EHA 2016 has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.


EHA 2016

Chemo-genomic interrogation reveals JAK sensitive subgroup in AML

Dr Vincent-Philippe Lavallée - Université de Montréal, Montréal, Canada

I’m presenting part of the data that is part of the Leucegene research project. As part of this project we have sequenced a large collection of AML, 415 primary AML samples, and we like to perform a comparative analysis with the transcriptome information and chemical screening. At this meeting I will present a specific subgroup of leukaemias that are characterised by biallelic CEBPA mutation.

Could you tell us about this subgroup, how they’re characterised?

This subgroup is a really defining subgroup as it is characterised as a definitive entity in the WHO classification because they are clustered in the cytogenetically normal karyotype acute myeloid leukaemia. Importantly they are associated to favourable clinical outcomes in general so the patients won’t be treated with allogenic stem cell transplantation in first complete remission but rather just consolidation with chemotherapy. But still up to 40% of the patients may relapse and die from the disease eventually.

And you mentioned that they had a favourable outcome, what kind of sensitivities do they have?

As part of overall survival?

Overall survival or I found in the abstract something to JAK inhibitory therapy especially.

Yes, so because of still this significant number of patients that will relapse or die from the disease we aimed in this project to find all the mutations that could be targetable by drug repurposing. So we investigated the mutational landscape and we identified a recurrent mutation in CSF3R which is the gene encoding the receptor of the granulocyte-colony stimulating factor. Those mutations are actually targetable because they signal through JAK-STAT signalling and so we performed that screen on JAK inhibitors.

How consistent was the expression of CSF3R mutant genes within the subtype? Completely across the board or was it…?

The frequency? Yes, we found 36% mutation involving this pathway, most importantly in CSF3R but also a CSF3R wild-type sample that was also mutated for another gene in this pathway called STAT5B.

With this new information from the transcriptome what would be the next step in developing either further trials, further investigations or further therapies towards it?

It’s more the chemical screen that provided us some information because we realised the chemical screen based on targeted inhibitors, JAK inhibitors and cytotoxic agents. In our analysis the cases that were mutated for CEBPA in general were more sensitive to the JAK inhibitors, the specific JAK inhibitors. So that provides a rationale for potential repurposing of those compounds in AML patients with biallelic CEBPA mutations.

Just in a more general sense, could I have your thoughts or opinions on bringing this kind of screening information to more clinics, to more subtypes, maybe even to more diseases?

Yes, this remains a highly research type project but for sure, at least in the project that we are… in the Leucegene project, we really divide AML subgroup by subgroup and for every type of genetic entity we try to see if there is any rationale to perform a targeted chemical screen base type of mutational profile that we find. We did that with AML leukaemias in the past, and we are doing it with additional subtypes in the present.