Modelling congenital neutropenia, a pre-leukemic bone marrow failure syndrome in zebrafish

Defects in zebrafish hematopoiesis reliably copy human blood diseases, making it a highly attractive model to develop therapeutic strategies. We study severe congenital neutropenia (CN), a blood disorder characterized by disrupted neutrophil development. Mutations in more than 20 genes are associated with CN, including HAX1, JAGN1, and CSF3R. Around 20% of CN patients develop leukemia. However, the underlying mechanisms are poorly understood. We use zebrafish to model CN and leukemogenic transformation in CN. Zebrafish harboring mutations in the HAX1, JAGN1, and CSF3R genes were generated using the CRISPR/Cas9 technology. Akin to CN patients, zebrafish deficient for HAX1 and JAGN1 displayed reduced neutrophil development, which could be rescued by G-CSF. Intriguingly, the introduction of truncated mutations in the CSR3R gene mimicking somatic mutations seen in CN/AML patients led to dysplastic hematopoiesis and high zebrafish lethality. Taken together, our established in vivo models enable studying CN and the leukemogenesis associated with CN. They can also serve as in vivo platform to perform drug screening and identify new therapeutic strategies for CN and leukemia development.

Publication History

Article published online:
17 May 2022