Our Research
AML & Leukemic Stem Cells
Acute myeloid leukemia (AML) is an aggressive form of blood cancer of the myeloid lineage. It is defined by the uncontrolled proliferation and clonal expansion of immature myeloblast cells in the blood and bone marrow, leading to hematopoietic failure. Although it is most commonly diagnosed in adults, this disease can also arise in children and young adults. Many different mutations can drive AML, leading to dysfunctional processes related to self-renewal, differentiation, proliferation, and cell death.
AML is sustained in a patient by leukemic stem cells (LSCs). These leukemic cells are rare and have similar characteristics to hematopoietic stem cells (HSCs). Like HSCs, LSCs are capable of self-renewal and differentiation and share gene expression programs. However, instead of generating normal cells, LSCs give rise to all the leukemic blasts in the patient. Thus, they must be eliminated to achieve a cure. Targeting LSCs and understanding their genetics and biology is the main interest of our lab.
AML develops in a stepwise manner, starting from a normal hematopoietic stem cell, to a pre-leukemic HSC clone to fully developed AML. To better understand this disease and respond with better treatment options, we first need to understand the evolution of AML. Initial mutations can occur at any stage during hematopoietic cell development, often originating in the HSC. These mutations can increase the HSC’s ability to self-renew and proliferate leading to clonal expansion. However, the mutations may not lead to any overt hematological malignancy. This phenomenon is often referred to as clonal hematopoiesis with indeterminant potential (CHIP) or age-related clonal hematopoiesis (ARCH) as it’s prevalence increases with age. Since HSCs persist for a lifetime, they can accrue additional mutations leading to leukemic transformation. These mutated genes are often called "drivers", as they drive the cells to develop into AML.
One group of key drivers for leukemogenesis are mutations in epigenetic regulators. Genes involved in DNA methylation (DNMT3A, TET2, IDH1/2), and histone modifications (ASXL1, EZH2) are often mutated in myeloid malignancies. In addition to epigenetic regulators, mutations in histone genes were first identified in pediatric gliomas and have since been identified in several cancer including hematological malignancies. Our lab has identified K27M/I mutations in histone H3 in AML and have observed that this event can occur at an early stage in leukemogenesis. We also demonstrated that K27 mutations are found in pre-leukemic hematopoietic stem cells (HSCs), are enriched in secondary AML, expand the functional human HSC pool and increase leukemic aggressiveness. Transcriptomic and epigenomic analysis determined that K27 mutations alter gene expression through a global decrease in promoter H3K27 tri-methylation and a gene-specific increase in H3K27 acetylation in leukemic cells (Boileau et al. Nat Commun, 2019).
Regulators of Stem Cells: Exosomes in AML
Glucocorticoids
DMSO
AML cells
Our research focuses on the fundamental biology of leukemic stem cells (LSCs) in pediatric and adult acute myeloid leukemia (AML). Despite the dramatic advances in blood cancer research, a major clinical challenge is counteracting therapy side effects and disease relapse. It is believed that treatment failure is in part due to the protective shield built by the tumour environment (i.e. hematopoietic niche), which supports the persistence of leukemia. Emerging cancer studies suggest that tumour-derived exosomes (TDE) are mediators of the protective effect of the niche and may be disease biomarkers and therapeutic targets. Exosomes are small, cell-derived entities involved in cell-to-cell communication and the exchange of valuable information through the environment. A significant number of studies have highlighted the biological impact of TDE on recipient cells leading to tumour growth, invasion, and metastasis as well as conferring drug resistance. Interestingly, studies on leukemia-derived exosomes have suggested their involvement in leukemia development and progression. However, the biological function of exosomes on LSCs remains to be fully deciphered, making them an emerging topic of great interest. Preliminary data generated in our laboratory provided new evidence that the uptake of TDE differs between leukemic populations, suggesting a structured exchange of information within the leukemic environment. Our main goal is to investigate the functional role of exosomes on cell-to-cell communication within the leukemia environment.
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The standard of care for AML consists of aggressive and cytotoxic drugs. Children with AML receive intensive chemotherapies that may result in future complications, such as infertilities and secondary cancers. On the other hand, elderly patients may be unable to withstand this intensive chemotherapy and either succumb to the disease or the treatment. Despite achieving remission, many patients eventually relapse with a more aggressive form of this disease and succumb to it. This is partially driven by the chemo-resistant nature of leukemic stem cells (LSCs) that are not fully eradicated by standard therapy due to their quiescent state and residing in a protective bone marrow niche. Hence, novel specific therapies targeting leukemic stem cell biology are needed to eliminate the disease and avoid reoccurrence. From our lab, Laverdière, I. & Boileau, M., et al., 2018 used an in silico and novel in vitro approach and identified numerous anti-LSC compounds that spare HSCs, including 3 glucocorticoids: mometasone, halcinonide, and budesonide that induce terminal differentiation of LSC-enriched populations. We aim to further investigate the role of the glucocorticoids and are preforming large high-throughput screens to identify other anti-LSC compounds against AML LSCs.
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