Transmission and expansion of HOXB4-induced leukemia in two immunosuppressed dogs: implications for a new canine leukemia model.
OBJECTIVE
There are currently no large animal models to study the biology of leukemia and development of novel antileukemia therapies. We have previously shown that dogs transplanted with homeobox B4 (HOXB4)-transduced autologous CD34(+) cells developed myeloid leukemia associated with HOXB4 overexpression. Here we describe the transmission, engraftment, and expansion of these canine leukemia cells into two genetically unrelated, immunosuppressed dogs.


METHODS
Two dogs immunosuppressed after major histocompatibility complex-haploidentical hematopoietic cell transplantation and exhibiting mixed donor-host chimerism were accidentally infused trace amounts of HOXB4-overexpressing leukemia cells from a third-party dog.


RESULTS
Six weeks after infusion of HOXB4-overexpressing leukemia cells, these two dogs rapidly developed myeloid leukemia consisting of marrow and organ infiltration, circulating blasts, and, in one dog, chloromatous masses. Despite neither of these dogs sharing any dog leukocyte antigen haplotypes with the sentinel case, the HOXB4-transduced clones engrafted and proliferated without difficulty in the presence of immunosuppression. Chimerism studies in both dogs confirmed that donor and, in one case, host hematopoietic cell engraftment was lost and replaced by third-party HOXB4 cells.


CONCLUSIONS
The engraftment and expansion of these leukemia cells in dogs will allow studies into the biology of leukemia and development and evaluation of novel antileukemia therapies in a clinically relevant large animal model.
Thakar
Monica S
MS
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Zhang
Xiao-Bing
XB
Beard
Brian C
BC
Sale
George E
GE
Santos
Erlinda B
EB
Peterson
Laura
L
Kiem
Hans-Peter
HP
Sandmaier
Brenda M
BM
D000059:Accidents; D000818:Animals; D002404:Catheterization / Q000009:adverse effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004285:Dogs; D004866:Equipment Contamination; D005440:Fluid Therapy / Q000295:instrumentation; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000633:toxicity; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000633:toxicity*; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D018598:Minisatellite Repeats; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000637:transplantation; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics / Q000633:toxicity*
C090460:HOXB4 protein, human; D015395:Histocompatibility Antigens Class I; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C039692:histocompatibility antigen DLA; D049452:Green Fluorescent Proteins