signature=1c8d2dcd7a2ea3070412e7a02e16ca14,The fetal pathogenesis of Down syndrome-associated leukae...

摘要：

Children with Down syndrome (DS; trisomy 21) have markedly increased susceptibility to acute megakaryoblastic leukaemia (AMKL) and acute lymphoblastic leukaemia (ALL) which, at least for AMKL, have their origin in fetal life. My project aims to identify and characterise abnormalities in haematopoiesis in human fetal DS in order to understand how T21 leads to the increase in leukaemia susceptibility in DS. Since both AMKL and ALL are increased in DS, I first investigated the hypothesis that T21 perturbs the earliest multipotent progenitor (MPP) and/or haematopoietic stem cell (HSC) compartment and found that the HSC compartment is always expanded in DS FL compared to normal FL and that this had markedly increased CD7 expression. The DS FL HSC/ MPP compartment was also functionally abnormal with increased clonogenicity and megakaryocyte-erythroid potential and a distinct gene expression signature. Since no mutations in GATA1 or JAK2 were detected, my data support a direct role for T21 in the abnormalities of HSC number and function. To investigate whether differences in the FL microenvironment contribute to the abnormal HSC/myeloid progenitor compartment in DS FL, I analysed HSC/progenitors in fetal BM in DS by flow cytometry and in vitro assays. Although both MEP and myeloid progenitor/HSC clonogenicity and self-renewal were increased, this was less marked than in DS FL, indicating the effects of T21 are not limited to FL haematopoiesis but also supporting a role for the HSC/progenitor microenvironment. To investigate the role of T21 in initiation of ALL, I tested the hypothesis that T21 perturbs lymphopoiesis by characterising the lymphoid progenitor population in FL and fetal BM. I found a marked reduction in B progenitors, particularly at the committed B progenitor (CBP) level in DS FL and fetal BM which was confirmed by in vitro lymphoid cultures and gene expression patterns. These studies have characterised normal human fetal haematopoiesis for the first time and show that HSC, MPP and LMPP populations with full lymphoid differentiation are present in FL indicating that FL, and not just BM, is an active site of lymphopoiesis during fetal life which has implications for the origin of infant ALL. I have also demonstrated that T21 perturbs haematopoiesis at the HSC level, leading both to myeloid progenitor expansion and a block to B-cell differentiation. These findings increase our understanding of the role of T21 in initiating and maintaining leukaemia-initiating cells and suggest a tractable model for investigating the effects of aneuploidy on cell growth and differentiation.

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