Interferon regulatory factor (IRF)-8 is a critical transcription factor involved in the pathogenesis of myeloid neoplasia. However, the underlying mechanisms in vivo are not well known. Investigation of irf8-mutant zebrafish in this study indicated that Irf8 is evolutionarily conserved as an essential neoplastic suppressor through tight control of the proliferation and longevity of myeloid cells. Surviving irf8 mutants quickly developed a myeloproliferative neoplasm (MPN)-like disease with enhanced output of the myeloid precursors, which recurred after transplantation. Multiple molecules presented notable alteration and Mertk signaling was aberrantly activated in the hematopoietic cells in irf8 mutants. Transgenic mertk overexpression in Tg(coro1a:mertk) zebrafish recapitulated the myeloid neoplasia-like syndrome in irf8 mutants. Moreover, functional interference with Mertk, via morpholino knockdown or genetic disruption, attenuated the myeloid expansion phenotype caused by Irf8 deficiency. Therefore, Mertk signaling is a critical downstream player in the Irf8-mediated regulation of the progression of myeloid neoplasia. Our study extends the understanding of the mechanisms underlying leukemogenesis.
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We thank D Wang and Y Liu for technical assistances. This work was supported by the National Natural Science Foundation of China (31301198, 31271568 and 31571500); The National Key Basic Research Program of China (2015CB942802); The Fundamental Research Funds for the Central Universities (XDJK2017A015); The Outstanding Youth Science Foundation of Chongqing (cstc2011jjjq10003).
FZ, YS, YH and L Li designed the experiments. FZ, YS, YH, YZ and LZ performed most experiments. YL and YW provided technical assistance of flow cytometry, L Li wrote the manuscript, HL, L Luo, HH and HR discussed the results and commented on the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website