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Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish

Mengchang Xu, Yin Ye, Zhi'an Ye, Song'en Xu, Wei Liu, Jin Xu, Yiyue Zhang, Qifa Liu, Zhibin Huang, Wenqing Zhang
Haematologica 2019 July 9
31289206
Chronic myeloid leukemia is induced by the BCR/ABL1 oncogene, which encodes a protein tyrosine kinase. We examined the effect of direct overexpression of the human p210 BCR/ABL1 oncoprotein in zebrafish. Humanized p210 BCR/ABL1 protein was detectable in Tg(hsp70:p210BCR/ABL1 ) transgenic zebrafish embryos and adult kidney marrow. Transgenic zebrafish developed chronic myeloid leukemia, which could be induced via cells into recipients. The expression of human BCR/ABL1 promoted myeloid lineages in Tg(hsp70:p210BCR/ABL1 ) transgenic embryos. A total of 77 of 101 (76.24%) Tg(hsp70:p210BCR/ABL1 ) adult transgenic zebrafish (age 6 months to 1 year) developed chronic myeloid leukemia. Chronic myeloid leukemia in zebrafish showed a triphasic phenotype, similar to that in humans, involving a chronic phase predominantly characterized by neutrophils in various degrees of maturation, an accelerated phase with an increase in blasts and immature myeloid elements, and a blast phase with > 90% blasts in both the peripheral blood and kidney marrow. Tyrosine kinase inhibitors, as the standard drug treatment for human chronic myeloid leukemia, effectively reduced the expanded myeloid population in Tg(hsp70:p210BCR/ABL1 ) transgenic embryos. Moreover, we screened a library of 171 compounds and identified 10 new drugs against BCR/ABL1 kinase-dependent or -independent pathways that could also reduce lcp1 + myeloid cell numbers in Tg(hsp70:p210BCR/ABL1 ) transgenic embryos. In summary, we generated the first humanized zebrafish chronic myeloid leukemia model that recapitulates many characteristics of human chronic myeloid leukemia. This novel in vivo model will help to elucidate the mechanisms of chronic myeloid leukemia disease progression and allow high-throughput drug screening of possible treatments for chronic myeloid leukemia.

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