Researchers Discuss MLL-Rearranged Acute Myeloid Leukemias

Guy Sauvageau, MD, PhD, FRCP

Vincent-Philippe Lavallée, MD

Today, we are speaking with Vincent-Philippe Lavallée, a hematologist, and Guy Sauvageau, a research professor, both in the department of medicine at the University of Montreal in Quebec, Canada. Drs. Lavallée and Sauvageau recently published a study in Nature Genetics that mapped the transcriptome of a specific type of acute myeloid leukemia, and these leukemias have rearrangements in a gene called MLL or mixed-lineage leukemia.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: Before we get into the details of the study, Vincent-Phillippe, could you tell us about the approach used by your lab to map the gene expression of these MLL-mutated acute myeloid leukemia samples? What were the source of the samples and how were they processed and analyzed? Just briefly.

Dr. Lavallée: So, we were part of a project called the Leucegene Project, in which we performed RNA sequencing of a large cohort of primary AML samples. The samples come from the Quebec Leukemia Cell Bank, a cell bank that is located here in Montreal and the samples came from many places over the province of Quebec and so in that cohort, we had a few samples, 31, that had a fusion with the MLL gene and this analysis is about those leukemias.

OncoTherapy Network: Dr. Sauvageau, maybe you could tell us a little bit about what was known about MLL-rearranged acute myeloid leukemia prior to this work? Was there anything distinct about the clinical manifestation of these tumors or their genetics?

Dr. Sauvageau: Yes, there were quite a few studies done previously. Most noted one recently was from St. Jude’s on lymphoid MLL leukemias using next-generation sequencing. But, the study that Vincent did is indeed the first one that thoroughly analyzed MLL leukemias through an in-depth analysis of the transcriptome. So, the approach Vincent used was quite simple, but very effective. Instead of doing TCGA [The Cancer Genome Atlas], which was basically looking at the global transcriptome of all leukemias put together and then trying to find distinct mutations, he simply took the 31 MLL leukemias we had and he compared them to non-MLL specimens and this allowed him to identify rare mutations in the subgroups, and then through pathway analysis was able to identify further mutations on a given pathway and that is the original part.

OncoTherapy Network: Dr. Lavallée, could you tell us what the analysis revealed about these MLL-rearranged tumors?

Dr. Lavallée: So actually the transcriptome analysis revealed a distinct gene signature in the disease. For some of the genes, some were previously described from microarray datasets, so these were not a surprise, that was mostly a confirmation. But also, we identified the genes that were not previously described including some genes that were actually part of a cluster on chromosome 15. And quite interestingly, when we looked at the non-MLL fusion samples that also had a high expression for this cluster of genes, we found out that also some of these samples had another type of MLL rearrangement called an MLL partial tandem duplication. So, this transcriptome analysis unified the genetics of these two subtypes.

OncoTherapy Network: For both of you, in general, what is the major utility of these whole-genome genetic and expression analyses?

Dr. Sauvageau: Well, there are several different types of utilities, one of which is really to try to use a simple gene signature to carefully and definitely identify a given subset of leukemias. So in the era of personalized medicine, that is really critical. The second point is about prognostics. The idea here is to identify a subset of genes in a subset of the disease that will allow you to predict whether or not a patient will make it through their current therapy.

OncoTherapy Network: Then for Dr. Lavallée or both of you, are you following up this study with a more in-depth analysis of some of the important genes that may drive MLL-mutated leukemia? Or are there other follow up research you are doing?

Dr. Sauvageau: Well, in terms of genetics, we are certainly incorporating some of the genes Vincent identified into what we can call a diagnostic or prognostic kit for MLL leukemia. For example, one of these gene clusters allows you to really identify MLL leukemias in patients for whom standard or current genetics or cytogenetics would not allow you to identify. It is more the chemical aspect of the project that we are pursuing actively right now.

OncoTherapy Network: Is there anything else you wanted to add about either the follow-up work or the study?

Dr. Sauvageau: Maybe one other thing, which is that we also identified, and that is mostly the work of another postdoctoral fellow in the laboratory, Irène Baccelli, that there are two different groups of small molecules that interact together to specifically induce cell lethality in a subset of RAS-mutated MLL leukemias. So that is something that someone here or elsewhere trigger a phase I or phase II clinical studies with drugs.

OncoTherapy Network: Thank you so much to both of you for joining us today.

Dr. Sauvageau: Thank you.

Dr. Lavallée: Thank you.