The Nature of the Haematopoietic Stem Cell in Myelodysplastic Syndrome
The myelodysplastic syndromes (MDS) are a group of clonal
bone marrow stem cell disorders characterized by low blood cell
counts, an increased rate of apoptosis of haematopoietic progenitor
cells, and a high risk of transformation to acute leukaemia.
The goals of our research program are to gain insights into the
biology of MDS, and to use such insights to design rational and
effective MDS therapies.
The MDS stem cell advantage – EAR-2,
MDS, and AML
A central paradox in MDS biology is how the myelodysplastic
stem cell out-competes normal stem cells and comes to dominate
the bone marrow. We hypothesized that the competitive advantage
enjoyed by the MDS stem cell consists in an enhanced
capacity for self-renewal, and identified gene that mediate this
property in leukaemia cells. One of the genes we identified, EAR-
2, is also more highly expressed in MDS and leukaemia than in
normal bone marrow. We have found that EAR-2 expression
blocks differentiation of leukaemia cells in culture and leads to the
development of leukaemia when overexpressed in mouse bone
marrow. We are now studying the mechanism by which EAR-2
alters stem cell behaviour, and its role in the multistep pathogenesis
of MDS and AML.
When less is more – Candidate genes
in del(5q) and del(7q) MDS
Clonal cytogenetic abnormalities are present in more than 50% of
cases of MDS. Two of the most frequently seen abnormalities
involve involve deletions of large tracts of the long arms of
chromosomes 5 or 7. These deletions are thought to contribute
to the development of MDS by resulting in the loss of tumour
suppressor genes located on these chromosomes; however, the
identity of such tumour suppressor genes remains a mystery. We
are investigating two candidate MDS tumour suppressor genes:
SPARC (chromosome 5q), a mediator of the interactions between
the cell surface and the extracellular matrix, and HIPK2 (chromosome
7q), a serine/threonine kinase that has roles in the regulation
of proliferation and apoptosis.
Iron, oxidative stress, and the stem cell
Owing to the failure of normal haematopoiesis, patients with
myelodysplastic syndrome commonly require regular blood transfusions
in order to survive. This results in accumulation of iron,
which results in cellular damage via the generation of reactive
oxygen species (ROS). Since accumulation of ROS leads to HSC
senescence in mice, we have hypothesized that iron overload in
MDS patients creates a vicious cycle, in which iron deposition
results in ROS generation, leading to further impairment in
haematopoiesis, leading to even greater requirement for blood
transfusion. Furthermore, we believe the DNA-damaging effects
of ROS may contribute to the progression of MDS to AML. We
are conducting experiments to measure this phenomenon, and to
explore how it may be reversed by iron chelation and anti-oxidant
agents.
Graduate Students:
- Alan Chan
- Christine Ichim
Selected References:
Link to Pubmed Publications-
Chan LS, Wells RA. Manipulation of reciprocal salt bridges at the heterodimerization interface alters the dimerization properties of mouse RXRalpha and PPARgamma1. Biochem Biophys Res Commun. 2007 Jul13;358(4):1080-5.
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Ichim CV and Wells RA. First among equals: The cancer cell hierarchy. Leukemia and Lymphoma, 2006;47 (10):2017-27.
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Gu C, Teng T, and Wells RA. Synergistic effects of troglitazone in combination with cytotoxic agents in acute myelogenous leukaemia cells. Leukemia Research, 2006; 30; 1447-1451.
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Disperati P, Ichim CV, Tkachuk D, Chun K, Schuh AC, and Wells RA. Progression of myelodysplastic syndrome to acute lymphoblastic leukaemia: Implications for disease biology. Leukemia Research. 2006;30:233-9.
