BCR‐ABL translocation in a dog with chronic monocytic leukemia

Abstract

A 9-year-old female spayed mixed breed dog was evaluated at the University of Florida Small Animal Hospital for marked leukocytosis with no associated clinical signs. CBC abnormalities included marked leukocytosis (106,000/μL), marked monocytosis (78,000/μL), and the presence of 13% blast cells (13,832/μL), supporting a diagnosis of leukemia. Cytopenias and dysplastic changes in other cell lines were not present. Microscopic examination of bone marrow showed hypercellular uniparticles with a marginal increase in frequency of unclassified blast cells (2%), but was otherwise unremarkable. Flow cytometric immunophenotyping of blood cells determined that leukemic cells were CD45(+) , CD14(+) , and CD34(-) , and based on side scatter and CD45 reactivity the marrow contained 19% monoblasts. By immunocytochemical staining, the leukemic cells in the bone marrow were CD11b(+) , CD11c(+) , CD11d(+) , MHC-II(+) , MPO(+) , and CD34(-) . Fluorescence in situ hybridization (FISH) analysis of peripheral blood leukocytes documented a chromosomal translocation producing a BCR-ABL gene hybrid, similar to the "Philadelphia" chromosome abnormality recognized in human chronic myelogenous leukemia, as well as a phosphatase and tensin homolog (PTEN) gene deletion. Hydroxyurea therapy was attempted, but was ineffective; the dog died 7 months after initial presentation. Clinical and laboratory findings and the protracted course supported a diagnosis of chronic monocytic leukemia (CMoL) and, to our knowledge, this is the first case of CMoL with a BCR-ABL chromosomal abnormalitiy described in dogs. This may have clinical implications for treatment of dogs with chronic leukemias associated with particular genetic mutations. However, more case studies are needed to further characterize this disease.

DNA damage response and DNA repair – dog as a model?

“…Humans and dogs share an ancestrally related pathogenic basis for cancer, with pathognomonic genetic changes being conserved in both species [24]. As an example, the BCR-ABL fusion gene could be detected with fluorescence in situ hybridization (FISH) in canine chronic myelogenous leukemia (CML) and chronic monocytic leukemia, which is equivalent to the Philadelphia chromosome (with the BCR-ABL fusion) in human CML showing equal genomic break sites [24,25]. Besides similarities in protein-coding regions, it is important to keep in mind that the slight differences in the total amount of canine and human genetic material could result in different levels and regulations of the micro (mi) RNAs, which are becoming increasingly relevant.…”

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.…”

Partial cytogenetic response with toceranib and prednisone treatment in a young dog with chronic monocytic leukemia

“…Chronic myeloid leukemia (CML) is rare in the dog and diagnosis is challenging as criteria for veterinary CML are not well established [1][2][3][4][5][6][7][8][9][10][11]. Human CML is considered a chronic myeloproliferative disease that occurs because of a specific chromosomal translocation [4,12].…”

“…As many as 95% of human adult patients with CML are positive for the Philadelphia chromosome translocation [4,13]. This genetic mutation arises from a reciprocal translocation between the ABL gene on human chromosome 9 and the BCR gene on human chromosome 22 [1,13]. The BCR-ABL translocation results in the production of a BCR-ABL fusion protein with aberrant tyrosine kinase activity.…”

“…A corresponding mutation to the Philadelphia chromosome in humans has been identified in dogs and is referred to as the Raleigh chromosome [13,15]. BCR-ABL translocation was identified in the reported dog and has been reported previously in dogs with CML [13,16], chronic monocytic leukemia (CMoL) [1], chronic myelomonocytic leukemia [17], and acute myeloblastic leukemia [18]. BCR-ABL translocation was identified in the reported dog and has been reported previously in dogs with CML [13,16], chronic monocytic leukemia (CMoL) [1], chronic myelomonocytic leukemia [17], and acute myeloblastic leukemia [18].…”