The role of non-canonical Wnt signaling in normal hematopoietic stem/progenitor cell biology and in pediatric/young adult leukemia
Krista M. Heinonen, PhD
Krista Heinonen is a professor-researcher at INRS-Institut Armand Frappier in Laval, where she started her laboratory studying Wnt signaling in fetal and adult hematopoiesis in November 2011. She completed her PhD thesis with Wayne Lapp and Michel Tremblay at McGill University in 2006, working on monocyte/macrophage development and function during systemic inflammation in protein tyrosine phosphatase knockout mouse models and chronic graft-versus-host disease. Wishing to pursue her interest in hemato-lymphopoiesis and transplantation, she joined the laboratory of Claude Perreault at the Institute of Research in Immunology and Cancer, where she focused on the role of the secreted glycoprotein Wnt4 in early T cell development.
While acute lymphocytic leukemia is most frequent in children, myelocytic leukemias are more common in older adults, and in infants. It is tempting to propose that a part of the differences between age groups could be attributed to intrinsic differences in the leukemia initiating cell, i.e. the hematopoietic stem/progenitor cell (HSPC). The adult stem cells are generally characterized as quiescent or dormant, and their number remains constant under normal conditions. Fetal and neonatal stem cells not only proliferate at a higher pace but they also divide in a manner that will increase their number. Aging stem cells also undergo proliferative expansion, although in their case an increase in numbers is associated with a loss of function. Nevertheless, the old and the very young stem cells would appear to have something in common, and the cell cycle characteristics and the replicative capacity of the HSPCs could have an impact on the latency period and type of leukemia produced.
The bridge between Krista’s postdoctoral work and future research lies in the capacity of Wnt4 to expand fetal liver hematopoietic stem/progenitor cells (HSPCs) in culture. Further, while it had only a limited effect on bone marrow HSPCs in the young adult mouse, lack of Wnt4 blunted the expansion of HSPCs in old bone marrow. Thus, the role of Wnt4 in HSPC expansion was age-dependent and its maximum effect correlated with stages of HSPC proliferation in the fetal liver and old bone marrow. The signaling pathway activated by Wnt4 in fetal liver cells and immature thymocytes was independent of the traditional, or canonical, Wnt signaling molecules; rather, it required the receptor Frizzled 6, which in epithelial cells has been associated with the establishment and maintenance of cellular polarity and proper tissue organization. These features are also posited as important for stem cell identity.
Thus, the main research focus of Krista’s laboratory is on the age-dependent role of Wnt4/Frizzled 6 axis, and other potential players in the so-called planar cell polarity pathway, on stem/progenitor cell proliferation and myelo-monocytic differentiation. Although the initial studies are done in mouse models, her ultimate goal will be to compare normal human stem/progenitor cells and leukemic cells at different ages, ranging from infant to the elderly.
These studies should shed light onto the molecular differences between infant and adult hematopoietic stem/progenitor cells with two perspectives: 1) comparing expanding (fetal liver) and quiescent (adult bone marrow) cells may reveal novel molecules of interest for the amplification of HSPC in culture; and 2) improved understanding of the differences in the potential leukemia initiating cells in pediatric vs adult leukemia should facilitate the design of more targeted therapies.