The fetal pathogenesis of Down syndrome-associated leukaemias
Author(s)
Roy, Anindita
Type
Thesis
Abstract
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.
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.
Date Issued
2010-12
Date Awarded
2011-07
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Roberts, Irene
Sponsor
Leukaemia & Lymphoma Research
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)