The Monteiro group employed a zebrafish fish model to replicate what happens in patients who inherit the loss of one allele of the GATA2 gene who develop bone marrow failure and leukaemia. Zebrafish lacking a transcriptional enhancer needed for efficient GATA2 expression exhibit a gradual loss of myeloid blood cells, a skewing towards red blood cells, and an AML-like syndrome.
Cell Reports 42:112571 (2023). Christopher B Mahony, Lucy Copper, Pavle Vrljicak, Boris Noyvert, Chrystala Constantinidou, Sofia Browne, Yi Pan, Claire Palles, Sascha Ott, Martin R Higgs, Rui Monteiro. Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency. doi: https://doi.org/10.1016/j.celrep.2023.112571
GATA2 deficiency is a rare genetic bone marrow disorder in which patients are at increased risk of blood cancers. This is likely due to (i) GATA2-deficient blood stem cells in bone marrow producing significantly fewer immune cells used to fight infection, and (ii) the GATA2 gene mutation resulting in impaired activity of genes that are involved in repairing ongoing damage to their DNA.
In humans, GATA2 haploinsufficiency due to mutations in coding or enhancer regions causes hematopoietic disorders collectively referred to as GATA2 deficiency syndromes. 75% of patients with inherited germline GATA2 mutations develop early-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
In the zebrafish model employed here, both alleles of an enhancer controlling the gata2a locus were deleted. This generated a bona fide model of GATA2 deficiency that shows marrow hypocellularity, neutropenia, increased susceptibility to infections, and development of an AML-like phenotype in the adult kidney marrow.
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