A series of important observations on the genetic and molecular characteristics of two leukemia subtypes was just published in Nature Genetics by a multidisciplinary team comprising the Leucégène research group, a major project headed by Dr. Guy Sauvageau of the Institute for Research in Immunology and Cancer (IRIC) at the Université de Montréal and Dr. Josée Hébert of Maisonneuve-Rosemont Hospital (MRH). The results of the study also suggest the possibility of a new combinatorial therapeutic approach for certain leukemias.
The goal of the Leucégène project is to develop new tools for a more detailed classification of patients suffering from acute myeloid leukemia (AML) with a view to improving outcomes and more effectively guiding the choice of available treatment options. AML is a highly aggressive blood cancer that kills close to 1,000 people a year in Canada. Because this is a very complex cancer, current prognostic tests are imprecise in assessing risks and treatment choices in most patients.
The Leucégène team used next-generation DNA sequencing technologies to characterize genetic anomalies in over 400 AML samples from the Quebec Leukemia Cell Bank (QLCB). High-output screening approaches developed at IRIC were also used to study leukemia cell response to a number of chemical compounds acting on the cell signaling pathways often deregulated in these cancers. “This analysis represents an important effort at integrating IRIC's expertise in cell biology, genomics, bioinformatics and medicinal chemistry, and demonstrates how genetic and chemical approaches can reveal complementary information,” points out Dr. Vincent-Philippe Lavallée, postdoctoral fellow in the laboratory of Dr. Sauvageau and lead author of the article.
The study in question concentrated on two AML subtypes involving rearrangements of mixed lineage leukemia (MLL) and allowed for identification of a gene expression profile common to the two groups and including new markers specific to these types of leukemia. The LOC100289656 gene, among others, seems to have a diagnostic value since it led to the discovery of MLL rearrangements never seen before in patients who had not been originally recognized as belonging to this group. The data obtained also confirmed the presence of mutations in a number of genes already associated with AML, including those of the Ras signaling pathway, and identified for the first time recurrent mutations in the SPI1 gene. Finally, the chemical target demonstrated that MLL leukemia of the first group characterized by the presence of Ras mutations seems to have a heightened sensitivity to two types of molecule inhibitors, suggesting that a novel therapeutic approach combining these two types of drug could prove to be effective in certain patients. In the longer term, this sort of integrative approach should make possible a detailed analysis of other types of leukemia, as well as of solid tumors.
This study constitutes convincing validation of the chemogenomic approach developed by IRIC researchers and their colleagues. “A large-scale multifaceted project like this,” explain Drs. Sauvageau and Hébert, “the results of which will have a real impact on patient health, was made possible thanks to the resolute commitment of Genome Canada, Génome Québec and AmorChem to supporting personalized medicine approaches. We also have to call attention to the dedication of our multidisciplinary team of researchers and physicians at IRIC and at MRH.”
About this study
Lavallée VP, Baccelli I, Krosl J, Wilhelm B, Barabé F, Gendron P, Boucher G, Lemieux S, Marinier A, Meloche S, Hébert J and Sauvageau G., The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias, Nature Genetics, August 3, 2015.
About the participating organizations
Institute for Research in Immunology and Cancer
An ultra-modern research hub and training centre located in the heart of the Université de Montreal, the Institute for Research in Immunology and Cancer (IRIC) was created in 2003 to shed light on the mechanisms of cancer and discover new, more effective therapies to counter this disease. IRIC operates according to a model that is unique in Canada. Its innovative approach to research has already led to discoveries that will, over the coming years, have a significant impact on the fight against cancer. For more information: www.iric.ca
AmorChem Limited Partnership
About AmorChem L.P. AmorChem L.P. is a venture capital fund located in Montreal focused on investing in promising life science projects originating from Quebec-based universities and research centres. The principal limited partners of this fund are Investissement-Québec, FIER Partenaires, Fonds de solidarité FTQ and Merck & Co. This fund is the latest addition to the GeneChem portfolio of funds, a fund manager in existence since 1997. AmorChem's innovative business model involves financing research-stage projects to enable them to reach pre-clinical proof-of-concept (“POC”) in a semi-virtual mode within 18-24 months. The fund seeks to generate returns through a two-pronged exit strategy: sell projects having reached POC to large biotechnology or pharmaceutical companies; or bundle them into new spin-out companies. AmorChem using external resources will manage the projects. To that effect, AmorChem has established a strategic partnership with the Biotechnology Research Institute in order to access its R&D platforms. In addition, to enabling projects requiring small molecules as tools or drug leads, AmorChem has founded NuChem Therapeutics Inc., a medicinal chemistry contract-research company. For more information: www.amorchem.com
Genome Canada is a not-for-profit organization that acts as a catalyst for developing and applying genomics and genomic-based technologies, to create economic and social benefits for Canadians. Genome Canada connects ideas and people across public and private sectors to find new uses for genomics, invests in large-scale science and technology to fuel innovation, and translates discoveries into applications and solutions across key sectors of national importance, including health, agriculture, forestry, fisheries & aquaculture, energy, mining, and the environment. For more information: www.genomecanada.ca
Since May 2000, Génome Québec has been the driving force behind the development of genomics in Québec. By supporting over 80 projects and 900 researchers and managing the operations of the McGill University and Génome Québec Innovation Centre, Génome Québec is helping to accelerate the discovery of new applications for genomics in strategic areas, such as personalized health care, forestry, the environment and agrifood. The funds invested by Génome Québec are provided by the ministère de l'Économie, de l'Innovation et des Exportations du Québec, the Government of Canada, through Genome Canada, and private partners. For more information: www.genomequebec.com
Institute for Research in Immunology and Cancer - Université de Montréal
Tel: 514 343-7283