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Title: Modeling TEL-AML1 childhood acute lymphoblastic leukaemia using human pluripotent stem cells
Author: Richardson, S. E.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Childhood acute lymphoblastic leukaemia (cALL) is distinct from that in adults with higher incidence, better prognosis and a distinct mutational spectrum. One hypothesis for this difference is that cALL arises in transient cells unique to early human development. I explored this in ETV6-RUNX1 cALL where evidence from twins and neonatal heel prick testing has shown that this mutation arises in utero and is an initiating event. I hypothesised that human pluripotent stem cells (hPSCs) could model the developmental features of in utero B cell development. In vitro B cell differentiation of hPSCs produced both pre and proB cells, and a CD19-IL7R+ progenitor that switched from myeloid to lympho-myeloid priming during culture, akin to that identified in parallel studies of human fetal liver (FL). At the global transcriptional level the hPSC lymphoid hierarchy mapped closely with FL, with both separating from adult suggesting that hPSCs provide a developmentally relevant model of early FL B lymphopoiesis. I used CRISPR-directed homologous recombination to engineer the expression of ETV6-RUNX1 under the endogenous ETV6 promoter. ETV6-RUNX1 hPSCs displayed a partial block in B cell differentiation at the level of the CD19-IL7R+ progenitor. ETV6-RUNX1 expressing proB cells co-expressed an abnormal B-myeloid gene expression signature similar to that seen in the CD19-IL7R+ progenitor. These data support a model where expression of ETV6-RUNX1 inhibits lymphoid specification in an early FL CD19-IL7R+ lymphomyeloid progenitor, arresting B lineage differentiation and resulting in the production of myeloid-primed B cells. This may explain the propensity for aberrant myeloid antigen expression seen in cALL. ETV6-RUNX1 hPSCs provide a platform for the systematic evaluation of the contribution of additional mutations seen in cALL and may offer a tractable platform for drug screening. In conclusion I propose the human fetal CD19-IL7R+ lymphomyeloid progenitor as a candidate target cell for in utero pre-leukemic initiation in cALL.
Supervisor: Enver, T. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available