Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the oncogenic BCR-ABL fusion gene with increased ABL tyrosine kinase (TK) activity1. Transduction of primitive hematopoietic cells with the BCR-ABL oncoprotein creates cells that display many features of their BCR-ABL+ counterparts in CML patients. Inhibition of the TK activity of BCR-ABL by small molecule inhibitors (imatinib mesylate (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 insensitive to IM and other ABL inhibitors and are not eradicated by currently available agents1,3. 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 permanently 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 birth4. 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 initiation of early phase CML. Twenty-eight fetuses were injected intraperitoneally at 45-55 days of gestation with 2 × 104 to 105 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 recipients of 2 × 104 cells, hereafter referred to as BCR-ABL goats for brevity) and 5 goats transplanted with MIG-transduced cells (2-5 × 104 cells, hereafter referred to as MIG goats for brevity) were born alive and thus available for follow-up studies.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD