Developmentally regulated molecular programmes in human fetal haematopoietic cells cooperate with MLL-AF4 to drive infant acute lymphoblastic leukaemia
<p>Although advances in the treatment of childhood acute lymphoblastic leukaemia (ALL) mean that about 90% of children with ALL are now leukaemia-free 5 years on from their diagnosis, the prognosis for the subset of ALL that occurs within the first year of life, referred to as infant ALL, rema...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2021
|
| Subjects: |
| _version_ | 1826307342235336704 |
|---|---|
| author | Rice, S |
| author2 | Roberts, I |
| author_facet | Roberts, I Rice, S |
| author_sort | Rice, S |
| collection | OXFORD |
| description | <p>Although advances in the treatment of childhood acute lymphoblastic leukaemia (ALL) mean that about 90% of children with ALL are now leukaemia-free 5 years on from their diagnosis, the prognosis for the subset of ALL that occurs within the first year of life, referred to as infant ALL, remains dismal. The most common genetic driver of infant ALL is a chromosomal translocation that leads to rearrangement of
the Mixed Lineage Leukaemia (MLL) gene. In infant ALL, the MLL-rearrangement invariably arises in utero, and this single mutational hit in fetal life is sufficient to give rise to a leukaemia that is uniquely aggressive and treatment-refractory, even when compared to leukaemia in older children with the same MLL-rearrangement.
The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Moreover, the contribution of the particular human fetal haematopoietic progenitor in which the translocation occurs remains unexplored. In this DPhil project, I aimed to address the hypothesis that fetal-specific gene expression programmes cooperate with the most common MLL-rearrangement
in infants, MLL-AF4, to initiate and maintain infant ALL. I further aimed to identify the human fetal haematopoietic progenitor(s) that provide the permissive cellular context for leukaemia initiation. I found that CRISPR/Cas9 editing of primary human fetal liver (FL) cells to produce an MLL-AF4/t(4;11) chromosomal translocation gave rise to a leukaemia that replicated the aggressive phenotypic features of infant ALL, designated <sup>CRISPR</sup>MLL-AF4+ ALL. Using direct comparison
of the transcriptomes of human fetal and adult haematopoietic progenitor cells, I identified a fetal-specific gene signature and further showed that CRISPRMLL-AF4+ ALL and MLL-AF4 infant ALL patients, but not MLL-AF4 childhood ALL patients, maintain the expression of these fetal genes. Finally, I found that, in-keeping with the B-ALL phenotype of MLL-AF4 infant ALL, lymphoid primed progenitors provided the most permissive cellular context to give rise to <sup>CRISPR</sup>MLL-AF4+ ALL.</p> |
| first_indexed | 2024-03-07T07:01:51Z |
| format | Thesis |
| id | oxford-uuid:fb38d23d-0897-4a08-b39f-841141368d5f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:01:51Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:fb38d23d-0897-4a08-b39f-841141368d5f2022-03-29T16:32:24ZDevelopmentally regulated molecular programmes in human fetal haematopoietic cells cooperate with MLL-AF4 to drive infant acute lymphoblastic leukaemiaThesishttp://purl.org/coar/resource_type/c_db06uuid:fb38d23d-0897-4a08-b39f-841141368d5fLeukemiaGene editingEnglishHyrax Deposit2021Rice, SRoberts, IRoy, AMilne, T<p>Although advances in the treatment of childhood acute lymphoblastic leukaemia (ALL) mean that about 90% of children with ALL are now leukaemia-free 5 years on from their diagnosis, the prognosis for the subset of ALL that occurs within the first year of life, referred to as infant ALL, remains dismal. The most common genetic driver of infant ALL is a chromosomal translocation that leads to rearrangement of the Mixed Lineage Leukaemia (MLL) gene. In infant ALL, the MLL-rearrangement invariably arises in utero, and this single mutational hit in fetal life is sufficient to give rise to a leukaemia that is uniquely aggressive and treatment-refractory, even when compared to leukaemia in older children with the same MLL-rearrangement. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Moreover, the contribution of the particular human fetal haematopoietic progenitor in which the translocation occurs remains unexplored. In this DPhil project, I aimed to address the hypothesis that fetal-specific gene expression programmes cooperate with the most common MLL-rearrangement in infants, MLL-AF4, to initiate and maintain infant ALL. I further aimed to identify the human fetal haematopoietic progenitor(s) that provide the permissive cellular context for leukaemia initiation. I found that CRISPR/Cas9 editing of primary human fetal liver (FL) cells to produce an MLL-AF4/t(4;11) chromosomal translocation gave rise to a leukaemia that replicated the aggressive phenotypic features of infant ALL, designated <sup>CRISPR</sup>MLL-AF4+ ALL. Using direct comparison of the transcriptomes of human fetal and adult haematopoietic progenitor cells, I identified a fetal-specific gene signature and further showed that CRISPRMLL-AF4+ ALL and MLL-AF4 infant ALL patients, but not MLL-AF4 childhood ALL patients, maintain the expression of these fetal genes. Finally, I found that, in-keeping with the B-ALL phenotype of MLL-AF4 infant ALL, lymphoid primed progenitors provided the most permissive cellular context to give rise to <sup>CRISPR</sup>MLL-AF4+ ALL.</p> |
| spellingShingle | Leukemia Gene editing Rice, S Developmentally regulated molecular programmes in human fetal haematopoietic cells cooperate with MLL-AF4 to drive infant acute lymphoblastic leukaemia |
| title | Developmentally regulated molecular programmes in human fetal
haematopoietic cells cooperate with MLL-AF4 to drive infant acute
lymphoblastic leukaemia |
| title_full | Developmentally regulated molecular programmes in human fetal
haematopoietic cells cooperate with MLL-AF4 to drive infant acute
lymphoblastic leukaemia |
| title_fullStr | Developmentally regulated molecular programmes in human fetal
haematopoietic cells cooperate with MLL-AF4 to drive infant acute
lymphoblastic leukaemia |
| title_full_unstemmed | Developmentally regulated molecular programmes in human fetal
haematopoietic cells cooperate with MLL-AF4 to drive infant acute
lymphoblastic leukaemia |
| title_short | Developmentally regulated molecular programmes in human fetal
haematopoietic cells cooperate with MLL-AF4 to drive infant acute
lymphoblastic leukaemia |
| title_sort | developmentally regulated molecular programmes in human fetal haematopoietic cells cooperate with mll af4 to drive infant acute lymphoblastic leukaemia |
| topic | Leukemia Gene editing |
| work_keys_str_mv | AT rices developmentallyregulatedmolecularprogrammesinhumanfetalhaematopoieticcellscooperatewithmllaf4todriveinfantacutelymphoblasticleukaemia |