Long-term deregulated human hematopoiesis in goats transplanted in utero with BCR-ABL-transduced lin-CD34＊ cord blood cells

Chronic myeloid leukemia （CML） is a clonal hemato poietic stem cell disorder characterized by the oncogenic BCR-ABL fusion gene with increased ABL tyrosine ki- nase （TK） activity [1]. Transduction of primitive hematopoietic cells with the BCR-ABL oncoprotein creates cells that display many features...

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Bibliographic Details
Published in:Cell research 2013-06, Vol.23 (6), p.859-862
Main Authors: Zeng, Fanyi, Huang, Shu-Zhen, Gong, Zhi-Juan, Chen, Mei-Jue, Baldwin, Don A, Hu, Wei, Qian, Hui, Yan, Jing-Bin, Wang, Juan, Xiao, Yan Ping, Chalandon, Yves, Ringrose, Ashley, Ren, Zhao-Rui, Eaves, Allen, Eaves, Connie, Jiang, Xiaoyan
Format: Article
Language:English
Subjects:
Animals
Antigens, CD34 - metabolism
Cord Blood Stem Cell Transplantation
Fetal Blood - cytology
Fusion Proteins, bcr-abl - genetics
Goats
Hematopoiesis
Humans
Letter to the Editor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Transplantation, Heterologous
WT1 Proteins - metabolism
人类
子宫
山羊
异种移植
慢性粒细胞白血病
放松管制
脐带
造血细胞
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Summary:Chronic myeloid leukemia （CML） is a clonal hemato poietic stem cell disorder characterized by the oncogenic BCR-ABL fusion gene with increased ABL tyrosine ki- nase （TK） activity [1]. Transduction of primitive hematopoietic cells with the BCR-ABL oncoprotein creates cells that display many features of their BCR-ABL＋ coun- terparts in CML patients. Inhibition of the TK activity of BCR-ABL by small molecule inhibitors （imatinib mesyl- ate （IM）, dasatinib and nilotinib） [2] causes impressive responses in chronic phase CML patients. Nevertheless, response failures, early relapses and the later emergence of IM-resistant disease remain significant problems for many patients. In particular, CML stem cells are insensi- tive to IM and other ABL inhibitors and are not eradi- cated by currently available agents [1, 3]. These findings underscore the importance of understanding the biology of CML stem/progenitor cells and their unique properties in vivo, in guiding the development of strategies to per- manently cure CML. We have used a new xenograft model that exploits the advantages of a long-living, large animal host, the goat, which can be transplanted in a preimmune state in utero and then followed for several years after birth [4]. We transplanted fetal goats in utero with BCR-ABL- transduced lin-CD34＋ human cord blood （CB） cells and analyzed 6 liveborn goats for persistent engraftment of GFP＋BCR-ABL＋ cells in multiple tissues and for initia- tion of early phase CML. Twenty-eight fetuses were injected intraperitoneally at 45-55 days of gestation with 2 x l04 to l0s transduced lin human CB cells （-85% were CD34＋, 20%-30% were GFP＋BCR-ABL＋）. Another 14 fetuses were similarly transplanted with control GFP- vector-transduced cells （MIG）. Both groups displayed a high rate of abortion （〉 50%）. Therefore, only 6 goats transplanted with BCR-ABL-transduced cells （all recipi- ents of 2 x 104 cells, hereafter referred to as BCR-ABL goats for brevity） and 5 goats transplanted with MIG-transduced cells （2-5 x 104 cells, hereafter referred to as MIG goats for brevity） were born alive and thus avail- able for follow-up studies. A group of 3 BCR-ABL goats and 2 MIG goats were sacrificed 3 weeks after birth. Fluorescence microscopy and confocal laser scanning microscopy revealed a large number of GFP＋ （BCR-ABL＋） cells in liver, kidney and lung from all three BCR-ABL goats （Supplementary in- formation, Figure S1A-S 1C）. FACS analysis also detect- ed GFP＋ （BCR-ABL＋） cells in suspens
ISSN:1001-0602
1748-7838
DOI:10.1038/cr.2013.60