Chromosome Research

, Volume 23, Issue 4, pp 681–708 | Cite as

Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation

  • Sarah C. Roode
  • Daniel Rotroff
  • Anne C. Avery
  • Steven E. Suter
  • Dorothee Bienzle
  • Joshua D. Schiffman
  • Alison Motsinger-Reif
  • Matthew Breen
Article

Abstract

Leukemia in dogs is a heterogeneous disease with survival ranging from days to years, depending on the subtype. Strides have been made in both human and canine leukemia to improve classification and understanding of pathogenesis through immunophenotyping, yet classification and choosing appropriate therapy remains challenging. In this study, we assessed 123 cases of canine leukemia (28 ALLs, 24 AMLs, 25 B-CLLs, and 46 T-CLLs) using high-resolution oligonucleotide array comparative genomic hybridization (oaCGH) to detect DNA copy number alterations (CNAs). For the first time, such data were used to identify recurrent CNAs and inclusive genes that may be potential drivers of subtype-specific pathogenesis. We performed predictive modeling to identify CNAs that could reliably differentiate acute subtypes (ALL vs. AML) and chronic subtypes (B-CLL vs. T-CLL) and used this model to differentiate cases with up to 83.3 and 95.8 % precision, respectively, based on CNAs at only one to three genomic regions. In addition, CGH datasets for canine and human leukemia were compared to reveal evolutionarily conserved copy number changes between species, including the shared gain of HSA 21q in ALL and ∼25 Mb of shared gain of HSA 12 and loss of HSA 13q14 in CLL. These findings support the use of canine leukemia as a relevant in vivo model for human leukemia and justify the need to further explore the conserved genomic regions of interest for their clinical impact.

Keywords

Leukemia Canine Chromosome Comparative genomic hybridization Comparative genomics 

Abbreviations

ALL

Acute lymphoblastic leukemia

AML

Acute myeloid leukemia

BAC

Bacterial artificial chromosome

CFA

Canis familiaris

CLL

Chronic lymphocytic leukemia

CML

Chronic myeloid leukemia

CMML

Chronic myelomonocytic leukemia

CMoL

Chronic monocytic leukemia

CNA

Copy number aberration

CNV

Copy number variant

FISH

Fluorescence in situ hybridization

GISTIC

Genomic Identification of Significant Targets in Cancer

HSA

Homo sapiens

LSA

Lymphosarcoma

oaCGH

Oligonucleotide array comparative genomic hybridization

SNP

Single nucleotide polymorphism

TZL

T zone lymphoma

WBC

White blood cell

Supplementary material

10577_2015_9475_MOESM1_ESM.xls (31 kb)
ESM 1(XLS 31 kb)
10577_2015_9475_MOESM2_ESM.xls (116 kb)
ESM 2(XLS 115 kb)

References

  1. Adam F, Villiers E, Watson S, Coyne K, Blackwood L (2009) Clinical pathological and epidemiological assessment of morphologically and immunologically confirmed canine leukaemia. Vet Comp Oncol 7(3):181–195CrossRefPubMedGoogle Scholar
  2. Angstadt AY, Thayanithy V, Subramanian S, Modiano JF, Breen M (2012) A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet 205(11):572–587CrossRefPubMedGoogle Scholar
  3. Argiropoulos B, Yung E, Humphries RK (2007) Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev 21(22):2845–2849CrossRefPubMedGoogle Scholar
  4. Avery A (2009) Molecular diagnostics of hematologic malignancies. Top Companion Anim Med 24(3):144–150CrossRefPubMedGoogle Scholar
  5. Baldus CD (2004) Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci 101(11):3915–3920PubMedCentralCrossRefPubMedGoogle Scholar
  6. Baldus CD, Burmeister T, Martus P et al (2006) High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults. J Clin Oncol 24(29):4714–4720CrossRefPubMedGoogle Scholar
  7. Barth TF, Martin-Subero JI, Joos S et al (2003) Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 101(9):3681–3686CrossRefPubMedGoogle Scholar
  8. Beroukhim R, Getz G, Nghiemphu L et al (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci 104(50):20007–20012PubMedCentralCrossRefPubMedGoogle Scholar
  9. Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905PubMedCentralCrossRefPubMedGoogle Scholar
  10. Breen M, Hitte C, Lorentzen TD et al (2004) An integrated 4249 marker FISH/RH map of the canine genome. BMC Genomics 5(1):65PubMedCentralCrossRefPubMedGoogle Scholar
  11. Breen M, Modiano JF (2008) Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans—man and his best friend share more than companionship. Chromosom Res 16(1):145–154CrossRefGoogle Scholar
  12. Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol/Hematol 57(3):245–253CrossRefGoogle Scholar
  13. Burnett R, Vernau W, Modiano J et al (2003) Diagnosis of canine lymphoid neoplasia using clonal rearrangements of antigen receptor genes. Vet Pathol 40(1):32–41CrossRefPubMedGoogle Scholar
  14. Cancer Genome Atlas Research Network (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368(22):2059–2074CrossRefGoogle Scholar
  15. Carramusa L, Contino F, Ferro A et al (2007) The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J Cell Physiol 213(2):511–518CrossRefPubMedGoogle Scholar
  16. Chapiro E, Leporrier N, Radford-Weiss I et al (2010) Gain of the short arm of chromosome 2 (2p) is a frequent recurring chromosome aberration in untreated chronic lymphocytic leukemia (CLL) at advanced stages. Leuk Res 34(1):63–68CrossRefPubMedGoogle Scholar
  17. Comazzi S, Gelain ME, Martini V et al (2011) Immunophenotype predicts survival time in dogs with chronic lymphocytic leukemia. J Vet Intern Med 21(1):100–106CrossRefGoogle Scholar
  18. Cruz C, Milner R, Alleman A et al (2011) BCR-ABL translocation in a dog with chronic monocytic leukemia. Vet Clin Pathol 40(1):40–47CrossRefGoogle Scholar
  19. Culver S, Ito D, Borst L et al (2013) Molecular characterization of canine BCR-ABL-positive chronic myelomonocytic leukemia before and after chemotherapy. Vet Clin Pathol 42(3):314–322PubMedCentralCrossRefPubMedGoogle Scholar
  20. Eisele L, Prinz R, Klein-Hitpass L et al (2009) Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia. Eur J Haematol 83(4):320–327CrossRefPubMedGoogle Scholar
  21. Figueiredo JF, Culver S, Behling-Kelly E, Breen M, Friedrichs KR (2012) Acute myeloblastic leukemia with associated BCR-ABL translocation in a dog. Vet Clin Pathol 41(3):362–368PubMedCentralCrossRefPubMedGoogle Scholar
  22. Flood-Knapik K, Durham A, Gregor T et al (2013) Clinical, histopathological and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol 11(4):272–286CrossRefPubMedGoogle Scholar
  23. Flynn JMM, Andritsos LA, Jones JA et al (2013) Dinaciclib (SCH 727965) is a novel cyclin-dependent kinase (CDK) inhibitor that exhibits activity in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 122(21):871Google Scholar
  24. Fonseca R, Van Wier S, Chng W et al (2006) Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia 20(11):2034–2040CrossRefPubMedGoogle Scholar
  25. Forestier E, Izraeli S, Beverloo B et al (2008) Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood 111(3):1575–1583CrossRefPubMedGoogle Scholar
  26. Friedman AD (2009) Cell cycle and developmental control of hematopoiesis by Runx1. J Cell Physiol 219(3):520–524CrossRefPubMedGoogle Scholar
  27. Futreal PA, Coin L, Marshall M et al (2004) A census of human cancer genes. Nat Rev Cancer 4(3):177–183PubMedCentralCrossRefPubMedGoogle Scholar
  28. Godbersen C, Agarwal VR, Paiva C, Brown JR, Danilov AV (2013) A novel cyclin dependent kinase inhibitor P1446A induces apoptosis of chronic lymphocytic leukemia B cells. Blood 122(21):1636Google Scholar
  29. Gryshchenko I, Hofbauer S, Stoecher M et al (2008) MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol 26(14):2252–2257CrossRefPubMedGoogle Scholar
  30. Gunnarsson R, Mansouri L, Isaksson A et al (2011) Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia. Haematologica 96(8):1161–1169PubMedCentralCrossRefPubMedGoogle Scholar
  31. Hedan B, Thomas R, Motsinger-Reif A et al (2011) Molecular cytogenetic characterization of canine histiocytic sarcoma: a spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior. BMC Cancer 11(1):201PubMedCentralCrossRefPubMedGoogle Scholar
  32. John LB, Ward AC (2011) The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol 48(9–10):1272–1278CrossRefPubMedGoogle Scholar
  33. Juopperi T, Bienzle D, Bernreuter D et al (2011) Prognostic markers for myeloid neoplasms. Vet Pathol 48(1):182CrossRefPubMedGoogle Scholar
  34. Kay NE, Eckel-Passow JE, Braggio E et al (2010) Progressive but previously untreated CLL patients with greater array CGH complexity exhibit a less durable response to chemoimmunotherapy. Cancer Genet Cytogenet 203(2):161–168PubMedCentralCrossRefPubMedGoogle Scholar
  35. Klein U, Lia M, Crespo M et al (2010) The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17(1):28–40CrossRefPubMedGoogle Scholar
  36. Korz C, Pscherer A, Benner A et al (2002) Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Blood 99(12):4554–4561CrossRefPubMedGoogle Scholar
  37. Kuiper R, Schoenmakers E, Van Reijmersdal S et al (2007) High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 21(6):1258–1266CrossRefPubMedGoogle Scholar
  38. Kyoda K, Nakamura S, Matano S, Ohtake S, Matsuda T (1997) Prognostic significance of immunoglobulin heavy chain gene rearrangement in patients with acute myelogenous leukemia. Leukemia 11(6):803–806CrossRefPubMedGoogle Scholar
  39. Lam K, Zhang D-E (2012) RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci J Virt Libr 17:1120CrossRefGoogle Scholar
  40. Levine RL (2013) Molecular pathogenesis of AML: translating insights to the clinic. Best Pract Res Clin Haematol 26(3):245–248CrossRefPubMedGoogle Scholar
  41. Lindblad-Toh K, Wade CM, Mikkelsen TS et al (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438(7069):803–819CrossRefPubMedGoogle Scholar
  42. Logan AC, Vashi N, Faham M et al (2014) Immunoglobulin and T-cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplant relapse and survival. Biol Blood Marrow Transplant 20(9):1307–1313CrossRefPubMedGoogle Scholar
  43. Marcucci G, Maharry K, Whitman SP et al (2007) High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 25(22):3337–3343CrossRefPubMedGoogle Scholar
  44. Mullighan CG, Goorha S, Radtke I et al (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446(7137):758–764CrossRefPubMedGoogle Scholar
  45. Nicholas TJ, Baker C, Eichler EE, Akey JM (2011) A high-resolution integrated map of copy number polymorphisms within and between breeds of the modern domesticated dog. BMC Genomics 12(1):414PubMedCentralCrossRefPubMedGoogle Scholar
  46. Nowell P, Hungerford D (1961) Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst 27:1013PubMedGoogle Scholar
  47. Olshen AB, Venkatraman E, Lucito R, Wigler M (2004) Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5(4):557–572CrossRefPubMedGoogle Scholar
  48. Parkin B, Erba H, Ouillette P et al (2010) Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia. Blood 116(23):4958–4967PubMedCentralCrossRefPubMedGoogle Scholar
  49. Pede V, Rombout A, Vermeire J et al (2013) Expression of ZAP70 in chronic lymphocytic leukaemia activates NF-κB signalling. Br J Haematol 163(5):621–630CrossRefPubMedGoogle Scholar
  50. Pérez ML, Culver S, Owen JL et al (2013) Partial cytogenetic response with toceranib and prednisone treatment in a young dog with chronic monocytic leukemia. Anti-Cancer Drugs 24(10):1098–1103CrossRefPubMedGoogle Scholar
  51. Poorman K, Borst L, Moroff S, Roy S, Labelle P, Motsinger-Reif A, Breen M (2015) Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization. Chromosom Res 23:171–186Google Scholar
  52. R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  53. Radtke I, Mullighan CG, Ishii M et al (2009) Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci 106(31):12944–12949PubMedCentralCrossRefPubMedGoogle Scholar
  54. Rozovskaia T, Feinstein E, Mor O et al (2001) Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality. Oncogene 20(7):874CrossRefPubMedGoogle Scholar
  55. Schmetzer HM, Braun S, Wiesner D et al (2000) Gene rearrangements in bone marrow cells of patients with acute myelogenous leukemia. Acta Haematol 103(3):125–134CrossRefPubMedGoogle Scholar
  56. Seelig D, Avery P, Webb T et al (2014) Canine T-zone lymphoma: unique immunophenotypic features, outcome, and population characteristics. J Vet Intern Med 28(3):878–886CrossRefPubMedGoogle Scholar
  57. Shapiro SG, Raghunath S, Williams C, Motsinger-Reif A, Cullen JM, Liu T, Albertson D, Ruvolo M, Bergstrom Lucas A, Jin J, Knapp D, Schiffman JD and Breen M (2015) Canine urothelial carcinoma: genomically aberrant and comparatively relevant. Chromosom Res 23:311–331Google Scholar
  58. Strefford JC (2006) Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Proc Natl Acad Sci 103(21):8167–8172PubMedCentralCrossRefPubMedGoogle Scholar
  59. Suela J, Álvarez S, Cifuentes F et al (2007) DNA profiling analysis of 100 consecutive de novo acute myeloid leukemia cases reveals patterns of genomic instability that affect all cytogenetic risk groups. Leukemia 21(6):1224–1231CrossRefPubMedGoogle Scholar
  60. Suter S, Small G, Seiser E et al (2011) FLT3 mutations in canine acute lymphocytic leukemia. BMC Cancer 11(1):38PubMedCentralCrossRefPubMedGoogle Scholar
  61. Suzuki A, Iida S, Kato-Uranishi M et al (2005) ARK5 is transcriptionally regulated by the large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene 24(46):6936–6944CrossRefPubMedGoogle Scholar
  62. Swerdlow S, Campo E, Harris NL (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, FranceGoogle Scholar
  63. Szczepański T, Pongers-Willemse M, Langerak A and Van Dongen J (1999) Unusual immunoglobulin and T-cell receptor gene rearrangement patterns in acute lymphoblastic leukemias. Mechanisms of B cell neoplasia 1998, Springer: 205–215Google Scholar
  64. Tang J, Le S, Sun L et al (2010) Copy number abnormalities in sporadic canine colorectal cancers. Genome Res 20(3):341–350PubMedCentralCrossRefPubMedGoogle Scholar
  65. Thomas R, Duke SE, Karlsson EK et al (2008) A genome assembly-integrated dog 1 Mb BAC microarray: a cytogenetic resource for canine cancer studies and comparative genomic analysis. Cytogenet Genome Res 122(2):110–121PubMedCentralCrossRefPubMedGoogle Scholar
  66. Thomas R, Duke SE, Wang HJ et al (2009) ‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors. J Neuro-Oncol 94(3):333–349CrossRefGoogle Scholar
  67. Thomas R, Seiser EL, Motsinger-Reif A et al (2011) Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin’s lymphomas. Leuk Lymphoma 52(7):1321–1335PubMedCentralCrossRefPubMedGoogle Scholar
  68. Thomas R, Borst L, Rotroff D et al (2014) Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma. Chromosome Res 22(3):305–319CrossRefPubMedGoogle Scholar
  69. Tong W-G, Chen R, Plunkett W et al (2010) Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol 28(18):3015–3022CrossRefPubMedGoogle Scholar
  70. Usher S, Radford A, Villiers E, Blackwood L (2009) RAS, FLT3, and C-KIT mutations in immunophenotyped canine leukemias. Exp Hematol 37(1):65–77CrossRefPubMedGoogle Scholar
  71. Vernau W, Moore P (1999) An immunophenotypic study of canine leukemias and preliminary assessment of clonality by polymerase chain reaction. Vet Immunol Immunopathol 69(2–4):145–164CrossRefPubMedGoogle Scholar
  72. Villiers E, Baines S, Law AM, Mallows V (2006) Identification of acute myeloid leukemia in dogs using flow cytometry with myeloperoxidase, MAC387, and a canine neutrophil-specific antibody. Vet Clin Pathol 35(1):55–71CrossRefPubMedGoogle Scholar
  73. Weiss DJ, Wardrop KJ (eds) (2011) Schalm’s veterinary hematology. Wiley, AmesGoogle Scholar
  74. Welch JS, Ley TJ, Link DC et al (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278PubMedCentralCrossRefPubMedGoogle Scholar
  75. Wilkerson MJ (2012) Principles and applications of flow cytometry and cell sorting in companion animal medicine. Vet Clin N Am Small Anim Pract 42(1):53–71CrossRefGoogle Scholar
  76. Williams M, Avery A, Lana S et al (2008) Canine lymphoproliferative disease characterized by lymphocytosis: immunophenotypic markers of prognosis. J Vet Intern Med 22(3):596–601CrossRefPubMedGoogle Scholar
  77. Winkler D, Schneider C, Kröber A et al (2005) Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL). Leukemia 19(7):1211–1215CrossRefPubMedGoogle Scholar
  78. Withrow SJ, Vail DM, Page RL (2013) Withrow & MacEwen’s small animal clinical oncology. Elsevier Saunders, St. LouisGoogle Scholar
  79. Wong P, Iwasaki M, Somervaille TC, So CWE, Cleary ML (2007) Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev 21(21):2762–2774PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Sarah C. Roode
    • 1
  • Daniel Rotroff
    • 2
  • Anne C. Avery
    • 3
  • Steven E. Suter
    • 4
    • 5
    • 6
  • Dorothee Bienzle
    • 7
  • Joshua D. Schiffman
    • 8
    • 9
  • Alison Motsinger-Reif
    • 2
    • 5
  • Matthew Breen
    • 1
    • 5
    • 6
  1. 1.Department of Molecular Biomedical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Bioinformatics Research Center, Department of StatisticsNorth Carolina State UniversityRaleighUSA
  3. 3.Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical ScienceColorado State UniversityFort CollinsUSA
  4. 4.Department of Clinical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  5. 5.Center for Comparative Medicine and Translational ResearchNorth Carolina State UniversityRaleighUSA
  6. 6.Cancer Genetics Program, Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA
  7. 7.Department of PathobiologyUniversity of GuelphGuelphCanada
  8. 8.Department of PediatricsUniversity of UtahSalt Lake CityUSA
  9. 9.Department of Oncological Sciences, Center for Children’s Cancer Research, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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