Acute Myeloid Leukemia


Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. It remains an important cause of cancer related deaths in adolescent and young adults in Canada1.

In Canada, approximately 1000 patients with AML die each year. The clinical outcome of AML is poor with an overall 5-year relative survival of 25% and the majority of patients will experience relapse within 2 to 3 years2.

There are several unmet needs in AML diagnosis and therapy. Accurate prognostic tools to better orient patients to receive the optimal therapy are currently unavailable for more than half of AML patients. There is also an urgent need to develop novel and effective therapeutic strategies for high-risk or refractory/relapsing patients and for patients unfit to receive intensive therapy.

1. The Leucegene Project


The Leucegene project aims at redefining AML classification and prognosis using RNA-sequencing of primary AML samples. We now have established the comprehensive mutational and cytogenetic landscape of 437 primary AML samples.

The project can be divided in 5 main goals:

1. Novel Prognostic Classification of acute myeloid leukemia (AML): improving prognostic classification of AML using RNA-sequencing of a large cohort of BCLQ AML samples from diverse cytogenetic subgroups.

2. Minimal Residual Disease: identifiying better MRD markers to predict increased risk of relapse.

3. Chemogenomics: screening the in vitro biological responses of primary human AML cells to various collections of chemical compounds.

4. Bioinformatics: developing predictive tools that will make use of clinical observations and chemogenomic measures of patient samples to provide guidance to clinicians in selecting treatment.

5. GE3LS: highlighting the strengths and weaknesses of the Canadian federal and provincial regulatory approval models and outline the criteria for the legal and ethical recognition of study deliverables.

Visit the Leucegene project website for more details.

2. Identification of novel in vitro conditions to grow LSC


An important consideration in the field of leukemia stem cells (LSCs) is to define culture condition that best mimic the in vivo microenvironment. LSCs rapidly differentiate when introduced in culture. This hampers our ability to conduct cell-based high-throughput lethality screens and partly explains the lack of success in drug development for this disease.

To overcome these constraints we conducted a high-throughput screening and identified small molecules that inhibit differentiation and support LSC activity in vitro3. The first class of compounds identified, represented by SR1, inhibits the aryl hydrocarbon receptor (AhR) pathway. Interestingly this pathway is rapidly upregulated when cells are introduced in culture with obvious and rapid cell differentiation. A second compound, UM729, in combination with SR1 was shown to better maintain LSC activity in vitro. UM729 lacks AhR suppressor activity, which indicates that at least 2 different pathways are involved. These 2 compounds define the best culture conditions for improved ex vivo culture of primary human AML cells.

Unfortunately, approximately 30% of specimens respond poorly to these molecules suggesting that a 3rd pathway is operational in securing LSC self-renewal divisions. That is why we continue to screen new molecules and investigate our best hits.

3. Lead compounds and therapeutic targets for Hox-Meis leukemia


Deregulated expression of HOX, MEIS and PBX genes represents one of the most frequent molecular anomalies in human leukemia and is associated with adverse prognosis. Over the years, our group has characterized several components involved in HOX-MEIS-PBX leukemia and paved the way to identify, test, and further develop small molecules and therapeutic targets for this disease.

Our hypothesis is that HOX-MEIS1-PBX is one of the most potent and prevalent oncogenic networks (or complexes) that cause AML in humans.

Our goal is to characterize the nature of these transforming complexes in primary AML specimens (aim 1); to document their value as therapeutic targets (aim 2), and to initiate mechanistic-based preclinical studies that will lead to therapeutic intervention specifically targeting the HMP network (aim 3).



References

  1. Canadian Cancer Statistics. 2014. http://www.cancer.ca/~/media/cancer.ca/CW/cancer information/cancer 101/Canadian cancer statistics/Canadian-Cancer-Statistics-2014--EN.pdf.

  2. National Cancer Institute. http://seer.cancer.gov/.

  3. Pabst C, Krosl J, Fares I, Boucher G, Ruel R, Marinier A, Lemieux S, H├ębert J, Sauvageau G. (2014). Identification of small molecules that support human leukemia stem cell activity ex vivo. Nature Methods. 11(4): 436-42.