The role of histone demethylases in modulating hematopoietic stem cell fate, in both normal and leukemic cells
Sonia Cellot, MD, RCPSC
Sonia Cellot began her training with a B.Sc. in Biochemistry at McGill University. She subsequently completed her medical studies at Université de Montréal, first in pediatrics, then in hematology. Following her specialty certifications, having developed a strong interest for hematopoietic stem cell (HSC) transplantation and myeloid leukemia, she pursued with a post-doctoral fellowship in Dr Guy Sauvageau’s laboratory, studying the genetic regulation of HSC. The level of expertise required to pursue a carrier as an independent researcher in this field led her to officially enrol in the Molecular Biology PhD program, at Université de Montréal, as of May 2006. Her research work can be classified into two poles, first the in vitro expansion of HSC, and second, the conduction of screens to unravel factors essential for HSC self-renewal. In parallel to graduate studies in fundamental sciences, for a period of two years, she also worked in the outpatient bone marrow transplant clinic of Maisonneuve- Rosemont hospital, on a weekly basis, to widen her clinical exposure in this field. This was followed by clinical duties as a pediatric haematologist at Ste-Justine Hospital, where her appointment ensures a clinician-scientist profile. To efficiently bridge the clinical and research sides, her institutional responsibilities encompass acute myeloid leukemias (AML), molecular diagnostics, and biobanking of pediatric AML samples, as part of the Quebec Leukemia Cell Bank (BCLQ) initiative, founded by Dr Josée Hébert at Maisonneuve-Rosemont Hospital in 2001. She is a co-investigator in this project with Dr Hébert, which is operational since 2010. Tissue samples from patients are serially banked (diagnosis, remission and relapse) along with cells from both parents. This public platform enables direct assessment of primary human leukemia, a critically needed tool to validate animal models of the disease.
The emergence of common determinants between normal and leukemic stem cells fuelled her motivation to better characterize these two cell populations, and of course, to distinguish them molecularly, leading to more tailored and targeted therapies. During the last part of her PhD, she has studied the role of an emerging class of enzymes, namely the histone demethylases, in regulating HSC cell fate. They are, as a group, antagonistic to MLL, a histone methylases, found to be mutated in nearly 80% of infant leukemia cases. A functional screen unravelled positive and negative regulators of stem cell activity among these family members. The aim of her future work will be to complete the molecular characterization of these discovered hits, both on murine HSC and leukemic stem cells. As the next validation step, their relevance in human stem cells and pediatric leukemia will be addressed using BCLQ samples, in collaboration with Dr Josée Hébert.
Hematopoietic stem cells (HSC), present at low frequency in bone marrow (~1/10 000 cells in mouse), sustain the continuous replenishment of mature blood elements throughout life. These primitive cells harbour two fundamental characteristics; first, they can undergo self-renewal, a type of cell division in which at least one of the daughter cells is identical to the parent, and second, they are pluripotent, i.e., they can differentiate in all blood lineages. The rare HSC are also responsible for resuming hematopoiesis in transplantation recipients, upon myeloablative chemotherapy. Because of their properties and long-term persistence in the body, in opposition to differentiated cells, they are vulnerable targets for malignant transformation events. Indeed, a leukemic cell can be viewed as undergoing aberrant self-renewal divisions, in association with a differentiation block. The molecular circuitry that governs HSC cell fate has proven difficult to unmask, given our limited capacity to isolate these cells in large numbers required to perform biochemical analyses. A better understanding of self-renewal is crucial to the development of HSC in vitro expansion strategies, which would benefit research purposes, but also gene therapy and stem cell transplantation, Stem cells are rapidly exhausted in culture, thus the impetus to define preservation conditions that would enable in vitro manipulation of HSC for therapeutical purposes. In addition, despite better immunological tolerance, cord blood use for stem cell transplantation is hindered by a scarce number of HSC present in these grafts, particularly for adult size recipients. In vitro HSC expansion methods would hence broaden the accessibility of cord blood units in the treatment of cancer to a larger number of patients. Dissecting the mechanisms underlying self-renewal also rimes with a greater possibility to chemically target leukemic cells.
Overall, the goal of this research project is to study the role of histone demethylases, an emerging class of epigenetic effectors, in modulating hematopoietic stem cell fate decisions. These studies were initiated largely based on the importance of MLL (histone methylase) in governing HSC self-renewal, and the recent implication of Jarid1a (histone demethylase) in a pediatric leukemic protein fusion. As an ultimate goal, this work could help in designing chemical compounds that would target the activity of these enzymes, with relevance to both leukemia and in vitro expansion of HSC. Indeed, this is already an active area of pharmacological investigation.