Molecular characterization of canine BCR‐ABL–positive chronic myelomonocytic leukemia before and after chemotherapy

Abstract

Genetic aberrations linked to tumorigenesis have been identified in both canine and human hematopoietic malignancies. While the response of human patients to cancer treatments is often evaluated using cytogenetic techniques, this approach has not been used for dogs with comparable neoplasias. The aim of this study was to demonstrate the applicability of cytogenetic techniques to evaluate the cytogenetic response of canine leukemia to chemotherapy. Cytology and flow cytometric techniques were used to diagnose chronic myelomonocytic leukemia in a dog. High-resolution oligonucleotide array comparative genomic hybridization (oaCGH) and multicolor fluorescence in situ hybridization (FISH) were performed to identify and characterize DNA copy number aberrations (CNAs) and targeted structural chromosome aberrations in peripheral blood WBC at the time of diagnosis and following one week of chemotherapy. At the time of diagnosis, oaCGH indicated the presence of 22 distinct CNAs, of which trisomy of dog chromosome 7 (CFA 7) was the most evident. FISH analysis revealed that this CNA was present in 42% of leukemic cells; in addition, a breakpoint cluster region-Abelson murine leukemia viral oncogene homolog (BCR-ABL) translocation was evident in 17.3% of cells. After one week of treatment, the percentage of cells affected by trisomy of CFA7 and BCR-ABL translocation was reduced to 2% and 3.3%, respectively. Chromosome aberrations in canine leukemic cells may be monitored by molecular cytogenetic techniques to demonstrate cytogenetic remission following treatment. Further understanding of the genetic aberrations involved in canine leukemia may be crucial to improve treatment protocols.

Integrated immunohistochemical and DNA copy number profiling analysis provides insight into the molecular pathogenesis of canine follicular lymphoma

“…We have shown previously that spontaneous haematologic malignancies of dogs exhibit genomic alterations that are evolutionarily conserved with those of their human counterparts, despite their highly contrasting genome organization . Notable among these are the BCR‐ABL chromosome rearrangement of chronic myelogenous leukaemia, and the MYC‐IGH translocation of Burkitt lymphoma .…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…RB1 deletions in chronic lymphocytic leukaemia and BCR-ABL fusion in chronic myeloid leukaemia (CML) were among the first cytogenetic aberrations detected in canine cancers that mirror the corresponding human cancers [107]. The BCR-ABL tyrosine kinase translocation (the so-called 'Raleigh chromosome' in dogs and 'Philadelphia chromosome' in humans) has since been demonstrated to be present in additional subtypes [108,109] and proven useful for monitoring cytogenetic remission in CMLs [110]. Another canine study included acute lymphoblastic leukaemia (ALL)/acute undifferentiated leukaemia (AUL) (N ¼ 11) and chronic lymphocytic leukaemia (CLL) (N ¼ 12) and demonstrated increased c-KIT expression in the ALL/AUL samples [111], offering the possibility of using tyrosine kinase inhibitors as a treatment option in canine leukaemia, an approach similar to that used for human leukaemia with tyrosine kinase-affected pathways.…”

Dysregulation of tyrosine kinases and use of imatinib in small animal practice

“…The BCR-ABL translocation has also been detected in three dogs with chronic monocytic leukaemia (Cruz Cardona et al, 2011;Culver et al, 2013;Pérez et al, 2013) and in one dog with acute myeloblastic leukaemia (Figueiredo et al, 2012) by FISH analysis. Although the nucleotide sequence of DNA fusion junctions for BCR-ABL translocations has not yet been analysed, these findings suggest the presence of BCR-ABL in a certain subset of leukaemia in dogs, which would make imatinib a potential therapeutic approach for these canine tumours, similar to humans.…”