Human fetal B-lymphopoiesis and acute lymphoblastic leukaemia: the impact of trisomy 21

O'Byrne, S

Abstract:: Background: Children with Down Syndrome (DS), caused by an extra copy of chromosome 21 (trisomy 21, T21) are at increased risk of developing acute myeloid leukaemia (ML-DS) and B lineage acute lymphoblastic leukaemia (ALL). This points to specific effects of T21 on haematopoietic stem and progenitor cell (HSPC) biology. In ML-DS, all cases originate in fetal cells and T21, together with a GATA1 mutation is essential for disease progression. By contrast, in DS-ALL,...
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APA Style

O'Byrne, S. (2019). Human fetal B-lymphopoiesis and acute lymphoblastic leukaemia: the impact of trisomy 21 [PhD thesis]. University of Oxford.

MLA Style

O'Byrne, S. Human Fetal B-Lymphopoiesis and Acute Lymphoblastic Leukaemia: the Impact of Trisomy 21. University of Oxford, 2019.

Chicago Style

O'Byrne, S. 2019. “Human Fetal B-Lymphopoiesis and Acute Lymphoblastic Leukaemia: the Impact of Trisomy 21.” PhD thesis, University of Oxford.
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Files:: OByrne_2019_Human_fetal_B-lymphopoiesis.pdf

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Authors

+ O'Byrne, S More by this author

Division:: MSD
Department:: Paediatrics
Department:: University of Oxford
Role:: Author

Contributors

+ Roberts, I

Department:: University of Oxford
Role:: Supervisor

+ Roy, A

Department:: University of Oxford
Role:: Supervisor

+ Bloodwise More from this funder

Funding agency for:: Roy, A

+ Lady Tata Memorial More from this funder

Funding agency for:: Roy, A

+ Department of Paediatrics, University of Oxford More from this funder

Funding agency for:: O'Byrne, S

Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Keywords:: Down Syndrome

Leukaemia

Haematology

B-lymphopoiesis

Haematopoiesis

Fetal
Subjects:: Down Syndrome

Leukaemia

Haematology
UUID:: uuid:e87954e1-e298-42ad-b26f-e771e4e6beeb
Deposit date:: 2020-01-15

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Description:: Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19+ B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB-progenitors and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal bone marrow (BM), where together they form >40% of the total hematopoietic stem cell/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% ± 0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB-progenitors upstream of ProB-progenitors, identifying them as the first B-lymphoid–restricted progenitor in human fetal life. Although fetal BM PreProB-progenitors and ProB-progenitors both give rise solely to B-lineage cells, they are transcriptionally distinct. As with their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors display a distinct, ontogeny-related gene expression pattern that is not seen in adult PreProB-progenitors, and they share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid–restricted progenitor in human fetal life and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.
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Description:: The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM + B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM + B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime.
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Description:: ASH 2019 abstract for poster presentation

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Licence:: Terms and Conditions of Use for Oxford University Research Archive

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Human fetal B-lymphopoiesis and acute lymphoblastic leukaemia: the impact of trisomy 21

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Human fetal B-lymphopoiesis and acute lymphoblastic leukaemia: the impact of trisomy 21

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