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Haematologica 2020 Volume 105(3):674-686
Chronic Myeloid Leukemia
Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish
Mengchang Xu,1 Yin Ye,2 Zhi’an Ye,1 Song’en Xu,1 Wei Liu,2 Jin Xu,2 Yiyue Zhang,2 Qifa Liu,3 Zhibin Huang,2 and Wenqing Zhang1,2
1Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University; 2Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology and 3Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
ABSTRACT
Chronic myeloid leukemia (CML) is induced by the BCR/ABL1 onco- gene, which encodes a protein tyrosine kinase. We examined the
effect of direct overexpression of the human p210 oncoprotein in zebrafish. Humanized p210BCR/ABL1 protein was detectable in Tg(hsp70: p210BCR/ABL1) transgenic zebrafish embryos and adult kidney marrow. Transgenic zebrafish developed CML, which could be induced via cells transplanted 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-1 year) developed CML. CML in zebrafish showed a triphasic phe- notype, similar to that in humans, involving a chronic phase predominantly characterized by neutrophils in various degrees of maturation, an accelerat- ed phase with an increase in blasts and immature myeloid elements, and a blast phase with >90% blasts in both the peripheral blood and kidney mar- row. Tyrosine kinase inhibitors, as the standard drug treatment for human CML, effectively reduced the expanded myeloid population in Tg(hsp70:p210BCR/ABL1) transgenic embryos. Moreover, we screened a library of 171 compounds and identified ten 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 CML model that recapitulates many characteristics of human CML. This novel in vivo model will help to elucidate the mechanisms of CML disease progression and allow high- throughput drug screening of possible treatments for this disease.
Introduction
Chronic myeloid leukemia (CML) is a malignant bone marrow proliferative tumor originating from hematopoietic stem cells (HSC), with an annual incidence of 1-2/100,000 and accounting for 15-20% of all adult leukemias.1 CML is charac- terized by uncontrolled proliferation of myeloid cells and their progenitors in the peripheral blood (PB) and bone marrow (BM).2 The development of CML progress- es from a chronic phase (CP) to an accelerated phase (AP), and finally to a blast phase (BP). Most patients in the CML-CP are clinically asymptomatic, but are diag- nosed with leukocytosis characterized by mature granulocytes in the PB and BM. Disease progression to AP and BP is accompanied by a severe reduction in cellular differentiation, with immature blasts displacing mature cells.3 The final transforma- tion phase can result in both lymphoblastic (25%) and myeloblastic (50%) sub- types, with a further 25% manifesting biphenotypic or undifferentiated pheno- types.4
The presence of the Philadelphia chromosome (Ph+) is an important diagnostic indicator for CML.5 It is generated by a reciprocal translocation between chromo- somes 9 and 22, referred to as t(9;22)(q34;q11).6 This translocation results in the BCR/ABL1 fusion gene, which is translated to the p210BCR/ABL1 oncoprotein in almost
BCR/ABL1
Correspondence:
WENQING ZHANG
mczhangwq@scut.edu.cn
ZHIBIN HUANG
huangzhb1986@scut.edu.cn
Received: January 4, 2019. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2019.215939
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/674
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