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We are interested in how the special properties of prenatal stem and progenitor cells provide the permissive cellular context for the development of leukaemia in early childhood. Our particular focus is on leukaemias in children with Down syndrome and the newborn.

Abnormal megakaryocytes from a trisomy 21 megakaryocyte progenitor colony, x100

The Developmental Haematology and Paediatric Leukaemia Group aims to identify developmentally-regulated, molecular and biological properties of fetal haematopoietic stem and progenitor cells.  We think these properties are likely to provide the permissive cellular context for preleukaemia and leukaemia in early childhood and are investigating the mechanisms which drive these changes. 


We mainly focus on trisomy 21-mediated perturbation of haematopoiesis and the impact of trisomy 21 on leukaemia initiation. Through immunophenotypic, functional and gene expression studies on primary haematopoietic stem/progenitor cells we showed that trisomy 21 itself causes abnormal development of a range of progenitor types (Tunstall-Pedoe et al, 2008; Roy et al, 2012).  These changes precede the acquisition of leukaemogenic mutations in young children with Down syndrome.


We, and others, also showed that children with Down syndrome who develop Myeloid Leukaemia of Down Syndrome (ML-DS) all have abnormalities in a gene (GATA1) which is crucial for normal blood development. Mutations in GATA1 cluster in the N-terminus (exons 2/3) and are often multiple (Alford et al, 2011). GATA1 mutations are present at an astonishingly high frequency (just over 25% of all babies with Down syndrome; Roberts et al, 2013) and are acquired before birth (Tamblyn et al, 2016). We are currently using in vitro and in vivo models to investigate why GATA1 mutations occur at such high frequency and why these mutations are only leukaemogenic in cells harbouring trisomy 21. This work is done in collaboration with the Vyas lab in the WIMM.


Through gene expression analysis we have shown that trisomy 21 causes genome-wide dysregulation of gene expression in haematopoietic stem/progenitor cells as well as mesenchymal stromal cells (MSC) and that no single gene or groups of genes on chromosome 21 appears to explain the haematopoietic abnormalities (Liu et al, 2015).  Single cell studies to dissect the functional and molecular differences between disomic and trisomic cells are in progress.


We have also been investigating the lymphoid defects caused by trisomy 21. B-lineage acute lymphoblastic leukaemia (B-ALL) is markedly increased in children with Down syndrome. One clue to the reasons for this lies with our observation that B-cell development is particularly severely affected by trisomy 21. We now want to identify the molecular mechanisms which explain how trisomy 21 produces these defects and how this contributes to leukaemogenesis in children with Down syndrome. 

More recently, in work led by Dr Andi Roy, a Bloodwise Clinician Scientist, we have begun to characterise the normal B-cell developmental hierarchy and the interplay between ontogeny-related changes in B-lymphopoiesis and the pathogenesis of infant ALL. Since infant ALL invariably originates before birth and MLL gene rearrangement is often sufficient to cause leukaemic transformation without additional genetic abnormalities, we are focusing on characterising the target cell populations responsible for in utero initiation. We hope this approach will allow us to identify pathways that can be targeted for future therapies in infant ALL. 

 a. Erythroid colony (BFU-e) grown from a single human Megakaryocyte-Erythroid Progenitor (MEP) cell.  b. Erythroblasts isolated from a single MEP-derived erythroid colony.  c. Single cell RNA sequencing of early human haematopoietic  stem and progenitor cells showing clustering by principal  lineages.  d. Liquid culture of a single myeloid progenitor cell after 14 days culture ex vivo.

a. Erythroid colony (BFU-e) grown from a single human Megakaryocyte-Erythroid Progenitor (MEP) cell.

b. Erythroblasts isolated from a single MEP-derived erythroid colony.

c. Single cell RNA sequencing of early human haematopoietic  stem and progenitor cells showing clustering by principal  lineages.

d. Liquid culture of a single myeloid progenitor cell after 14 days culture ex vivo.

Developmental Haematology and Childhood Leukaemia

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