Abstract
Human myeloid malignancies represent a substantial disease burden to individuals, with significant morbidity and death. The genetic underpinnings of disease formation and progression remain incompletely understood. Large-scale human population studies have identified a high frequency of potential driver mutations in spliceosomal and epigenetic regulators that contribute to malignancies, such as myelodysplastic syndromes (MDS) and leukemias. The high conservation of cell types and genes between humans and model organisms permits the investigation of the underlying mechanisms of leukemic development and potential therapeutic testing in genetically pliable pre-clinical systems. Due to the many technical advantages, such as large-scale screening, lineage-tracing studies, tumor transplantation, and high-throughput drug screening approaches, zebrafish is emerging as a model system for myeloid malignancies. In this review, we discuss recent advances in MDS and leukemia using the zebrafish model.
Highlights
Myeloid malignancies are clonal disorders of hematopoietic stem and progenitor cells in which there is bone marrow failure, an overgrowth of blasts, differentiation arrest, and lineage skewing
Most of the core regulators of hematopoiesis are evolutionarily conserved between teleosts, such as zebrafish, and mammals, such that findings in zebrafish can be directly translated into mouse and human systems
A subsequent study found that expression of the TEL exon 5-Janus kinase 2 (JAK2) exon 9 variant led to lymphoid-restricted defects, while expression of the TEL exon 5-JAK2 exon 12 variant produced myeloid-restricted phenotypes, consistent with prior clinical observations [59]. These results indicate that the lineage selection for the specific TEL-JAK2 variant occurs via regulation of the downstream signaling rather than at the level of the chromosomal aberration
Summary
Human myeloid malignancies represent a substantial disease burden to individuals, with significant morbidity and death. Large-scale human population studies have identified a high frequency of potential driver mutations in spliceosomal and epigenetic regulators that contribute to malignancies, such as myelodysplastic syndromes (MDS) and leukemias. The high conservation of cell types and genes between humans and model organisms permits the investigation of the underlying mechanisms of leukemic development and potential therapeutic testing in genetically pliable pre-clinical systems. Due to the many technical advantages, such as large-scale screening, lineage-tracing studies, tumor transplantation, and high-throughput drug screening approaches, zebrafish is emerging as a model system for myeloid malignancies. We discuss recent advances in MDS and leukemia using the zebrafish model
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