Development of zebrafish models for leukaemia
Acute myeloid leukaemia (AML) is a haematopoietic malignancy characterised by increased proliferation of immature myeloid progenitor cells and decreased differentiation. Recurrent loss of function mutations are seen in the cohesin complex genes namely, RAD21, SMC1, SMC3A and STAG2. In this project, I investigated the role of Stag1/2 in haematopoiesis using zebrafish. I generated loss of function germline zebrafish mutants for three of the four zebrafish stag paralogues using CRISPR-Cas9 mutagenesis. Characterisation of mutants revealed that the stag paralogues are sub-functionalised during embryogenesis and that stag1a and stag2b have non-redundant haematopoietic functions. As the presence of specific co-operating mutations is required for malignant transformation in AML, I also generated combinatorial cohesin mutations with two frequent co-occurring mutations namely, a novel tet2 mutation and RUNX1-RUNX1T1 translocation. Existing AML animal models fail to capture the haematopoiesis-restricted and somatic nature of mutations. To address this problem, I generated macrophage-restricted tet2 mutant and draculin-restricted stag2b mutant lines that generate continual de novo mutations by tissue-specific production of Cas9 mRNA. The novel mutant lines generated here are useful to elucidate synergistic disease mechanisms and identify therapeutic targets in AML.
|Date||Thursday, 28 November 2019|
|Time||1:00pm - 2:00pm|
|Event Category||Health Sciences|
|Location||D'ath lecture theatre, Hercus building|
|Contact Name||Dr Euan Rodger|