Acta Neuropathologica

, Volume 120, Issue 6, pp 731–743 | Cite as

MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas

  • Ruth G. Tatevossian
  • Bo Tang
  • James Dalton
  • Tim Forshew
  • Andrew R. Lawson
  • Jing Ma
  • Geoff Neale
  • Sheila A. Shurtleff
  • Simon Bailey
  • Amar Gajjar
  • Suzanne J. Baker
  • Denise SheerEmail author
  • David W. EllisonEmail author
Original Paper


Recent studies of genetic abnormalities in pediatric low-grade gliomas (LGGs) have focused on activation of the ERK/MAPK pathway by KIAA1549-BRAF gene fusions in the majority of pilocytic astrocytomas (PAs) and by rare mutations in elements of the pathway across histopathologically diverse LGGs. This study reports that MYB, an oncogene not previously implicated in gliomagenesis, is activated in a diverse subset of pediatric LGGs. The study cohort comprised 57 pediatric LGGs and a comparative cohort of 59 pediatric high-grade gliomas (HGGs). The LGG cohort included 34 PAs and 23 diffuse gliomas; fibrillary astrocytomas (n = 14), oligodendroglial tumors (n = 7), and angiocentric gliomas (n = 2). MYB copy number abnormalities were disclosed using Affymetrix 6.0 SNP arrays and confirmed using interphase fluorescence in situ hybridization. Novel MYB amplifications that upregulate MYB RNA and protein expression were demonstrated in 2/14 diffuse astrocytomas. In addition, focal deletion of the terminal region of MYB was seen in 1 of 2 angiocentric gliomas (AGs). Increased expression of MYB was demonstrated by quantitative RT-PCR and immunohistochemistry. MYB upregulation at the protein level was demonstrated in a proportion of diffuse LGGs (60%), pilocytic astrocytomas (41%), and HGGs (19%), but abnormalities at the genomic level were only a feature of diffuse gliomas. Our data suggest that MYB may have a role in a subset of pediatric gliomas, through a variety of mechanisms in addition to MYB amplification and deletion.


MYB Glioma Pediatric Amplification 



This work was supported by the Pediatric Low-Grade Astrocytoma (PLGA) Foundation, the American Lebanese Syrian Associated Charities (ALSAC), the Samantha Dickson Brain Tumour Trust, and Cancer Research, UK.


  1. 1.
    Arora RS, Alston RD, Eden TO et al (2009) Age-incidence patterns of primary CNS tumors in children, adolescents, and adults in England. Neuro Oncol 11:403–413CrossRefPubMedGoogle Scholar
  2. 2.
    Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602CrossRefPubMedGoogle Scholar
  3. 3.
    Bender TP, Kremer CS, Kraus M, Buch T, Rajewsky K (2004) Critical functions for c-Myb at three checkpoints during thymocyte development. Nat Immunol 5:721–729CrossRefPubMedGoogle Scholar
  4. 4.
    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 USA 104:20007–20012CrossRefPubMedGoogle Scholar
  5. 5.
    Beug H, von Kirchbach A, Doderlein G, Conscience JF, Graf T (1979) Chicken hematopoietic cells transformed by seven strains of defective avian leukemia viruses display three distinct phenotypes of differentiation. Cell 18:375–390CrossRefPubMedGoogle Scholar
  6. 6.
    Biedenkapp H, Borgmeyer U, Sippel AE, Klempnauer KH (1988) Viral myb oncogene encodes a sequence-specific DNA-binding activity. Nature 335:835–837CrossRefPubMedGoogle Scholar
  7. 7.
    Broniscer A, Baker SJ, West AN et al (2007) Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol 25:682–689CrossRefPubMedGoogle Scholar
  8. 8.
    Chung EY, Dews M, Cozma D et al (2008) c-Myb oncoprotein is an essential target of the dleu2 tumor suppressor microRNA cluster. Cancer Biol Ther 7:1758–1764PubMedGoogle Scholar
  9. 9.
    Clappier E, Cuccuini W, Kalota A et al (2007) The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 110:1251–1261CrossRefPubMedGoogle Scholar
  10. 10.
    Close J, Game L, Clark B et al (2004) Genome annotation of a 1.5 Mb region of human chromosome 6q23 encompassing a quantitative trait locus for fetal hemoglobin expression in adults. BMC Genomics 5:33. doi: 10.1186/1471-2164-5-33 CrossRefPubMedGoogle Scholar
  11. 11.
    De Carli E, Wang X, Puget S (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:2248 (author reply pp 2249)CrossRefPubMedGoogle Scholar
  12. 12.
    Dougherty MJ, Santi M, Brose MS et al (2010) Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. doi: 10.1093/neuonc/noq007
  13. 13.
    Forshew T, Tatevossian RG, Lawson AR et al (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218:172–181CrossRefPubMedGoogle Scholar
  14. 14.
    Fouladi M, Hunt DL, Pollack IF et al (2003) Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children’s Cancer Group high-grade glioma study CCG-945. Cancer 98:1243–1252CrossRefPubMedGoogle Scholar
  15. 15.
    Fuller CE, Perry A (2005) Molecular diagnostics in central nervous system tumors. Adv Anat Pathol 12:180–194CrossRefPubMedGoogle Scholar
  16. 16.
    Geraci M, Birch JM, Alston RD, Moran A, Eden TO (2007) Cancer mortality in 13 to 29-year-olds in England and Wales, 1981–2005. Br J Cancer 97:1588–1594CrossRefPubMedGoogle Scholar
  17. 17.
    Grovas A, Fremgen A, Rauck A et al (1997) The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer 80:2321–2332CrossRefPubMedGoogle Scholar
  18. 18.
    Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF (2010) Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119:641–649CrossRefPubMedGoogle Scholar
  19. 19.
    Huang AM, Rehm EJ, Rubin GM (2009) Recovery of DNA sequences flanking P-element insertions in Drosophila: inverse PCR and plasmid rescue. Cold Spring Harb Protoc 2009:pdb prot5199Google Scholar
  20. 20.
    Jones DT, Kocialkowski S, Liu L et al (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677CrossRefPubMedGoogle Scholar
  21. 21.
    Jones DT, Kocialkowski S, Liu L et al (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119–2123CrossRefPubMedGoogle Scholar
  22. 22.
    Kagawa N, Maruno M, Suzuki T et al (2006) Detection of genetic and chromosomal aberrations in medulloblastomas and primitive neuroectodermal tumors with DNA microarrays. Brain Tumor Pathol 23:41–47CrossRefPubMedGoogle Scholar
  23. 23.
    Kanner AA, Staugaitis SM, Castilla EA et al (2006) The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making. J Neurosurg 104:542–550CrossRefPubMedGoogle Scholar
  24. 24.
    Kauraniemi P, Hedenfalk I, Persson K et al (2000) MYB oncogene amplification in hereditary BRCA1 breast cancer. Cancer Res 60:5323–5328PubMedGoogle Scholar
  25. 25.
    Kreiger PA, Okada Y, Simon S et al (2005) Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas. Acta Neuropathol 109:387–392CrossRefPubMedGoogle Scholar
  26. 26.
    Lahortiga I, De Keersmaecker K, Van Vlierberghe P et al (2007) Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet 39:593–595CrossRefPubMedGoogle Scholar
  27. 27.
    Lawson AR, Tatevossian RG, Phipps KP et al (2010) RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort. Acta Neuropathol 120:271–273CrossRefPubMedGoogle Scholar
  28. 28.
    Lei W, Rushton JJ, Davis LM, Liu F, Ness SA (2004) Positive and negative determinants of target gene specificity in myb transcription factors. J Biol Chem 279:29519–29527CrossRefPubMedGoogle Scholar
  29. 29.
    Lipsick JS, Wang DM (1999) Transformation by v-Myb. Oncogene 18:3047–3055CrossRefPubMedGoogle Scholar
  30. 30.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedGoogle Scholar
  31. 31.
    Malaterre J, Mantamadiotis T, Dworkin S et al (2008) c-Myb is required for neural progenitor cell proliferation and maintenance of the neural stem cell niche in adult brain. Stem Cells 26:173–181CrossRefPubMedGoogle Scholar
  32. 32.
    McCabe MG, Ichimura K, Liu L et al (2006) High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 65:549–561CrossRefPubMedGoogle Scholar
  33. 33.
    Mitani Y, Li J, Rao PH et al (2010) Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: incidence, variability and clinicopathological significance. Clin Cancer Res 16:4722–4731Google Scholar
  34. 34.
    Mucenski ML, McLain K, Kier AB et al (1991) A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65:677–689CrossRefPubMedGoogle Scholar
  35. 35.
    Nakamura M, Shimada K, Ishida E et al (2007) Molecular pathogenesis of pediatric astrocytic tumors. Neuro Oncol 9:113–123CrossRefPubMedGoogle Scholar
  36. 36.
    Oh IH, Reddy EP (1999) The myb gene family in cell growth, differentiation and apoptosis. Oncogene 18:3017–3033CrossRefPubMedGoogle Scholar
  37. 37.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453CrossRefPubMedGoogle Scholar
  38. 38.
    Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812CrossRefPubMedGoogle Scholar
  39. 39.
    Peris-Bonet R, Martinez-Garcia C, Lacour B et al (2006) Childhood central nervous system tumours—incidence and survival in Europe (1978–1997): report from Automated Childhood Cancer Information System project. Eur J Cancer 42:2064–2080CrossRefPubMedGoogle Scholar
  40. 40.
    Persson M, Andren Y, Mark J et al (2009) Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci USA 106:18740–18744CrossRefPubMedGoogle Scholar
  41. 41.
    Pfister S, Janzarik WG, Remke M et al (2008) BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739–1749CrossRefPubMedGoogle Scholar
  42. 42.
    Pollack IF, Finkelstein SD, Burnham J et al (2003) Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort. Pediatr Neurosurg 39:114–121CrossRefPubMedGoogle Scholar
  43. 43.
    Pollack IF, Finkelstein SD, Burnham J et al (2001) Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort. Cancer Res 61:7404–7407PubMedGoogle Scholar
  44. 44.
    Preusser M, Hoischen A, Novak K et al (2007) Angiocentric glioma: report of clinico-pathologic and genetic findings in 8 cases. Am J Surg Pathol 31:1709–1718CrossRefPubMedGoogle Scholar
  45. 45.
    Qaddoumi I, Sultan I, Broniscer A (2009) Pediatric low-grade gliomas and the need for new options for therapy: why and how? Cancer Biol Ther 8:4–10PubMedGoogle Scholar
  46. 46.
    Qaddoumi I, Sultan I, Gajjar A (2009) Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database. Cancer 115:5761–5770CrossRefPubMedGoogle Scholar
  47. 47.
    Raghavan R, Balani J, Perry A et al (2003) Pediatric oligodendrogliomas: a study of molecular alterations on 1p and 19q using fluorescence in situ hybridization. J Neuropathol Exp Neurol 62:530–537PubMedGoogle Scholar
  48. 48.
    Ramsay RG, Gonda TJ (2008) MYB function in normal and cancer cells. Nat Rev Cancer 8:523–534CrossRefPubMedGoogle Scholar
  49. 49.
    Reifenberger G, Louis DN (2003) Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62:111–126PubMedGoogle Scholar
  50. 50.
    Rosenthal MA, Thompson MA, Ellis S, Whitehead RH, Ramsay RG (1996) Colonic expression of c-myb is initiated in utero and continues throughout adult life. Cell Growth Differ 7:961–967PubMedGoogle Scholar
  51. 51.
    Schiffman JD, Hodgson JG, Vandenberg SR et al (2010) Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res 70:512–519CrossRefPubMedGoogle Scholar
  52. 52.
    Sievert AJ, Jackson EM, Gai X et al (2009) Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 19:449–458CrossRefPubMedGoogle Scholar
  53. 53.
    Smith JS, Perry A, Borell TJ et al (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645PubMedGoogle Scholar
  54. 54.
    Stenman G, Andersson MK, Andren Y (2010) New tricks from an old oncogene: gene fusion and copy number alterations of MYB in human cancer. Cell Cycle 9:2986–2995CrossRefPubMedGoogle Scholar
  55. 55.
    Tatevossian RG, Lawson AR, Forshew T et al (2010) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222:509–514PubMedGoogle Scholar
  56. 56.
    Thomas MD, Kremer CS, Ravichandran KS, Rajewsky K, Bender TP (2005) c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity 23:275–286CrossRefPubMedGoogle Scholar
  57. 57.
    Wallrapp C, Muller-Pillasch F, Solinas-Toldo S et al (1997) Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Res 57:3135–3139PubMedGoogle Scholar
  58. 58.
    Xiao C, Calado DP, Galler G et al (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131:146–159CrossRefPubMedGoogle Scholar
  59. 59.
    Yan H, Bigner DD, Velculescu V, Parsons DW (2009) Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 69:9157–9159CrossRefPubMedGoogle Scholar
  60. 60.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773CrossRefPubMedGoogle Scholar
  61. 61.
    Zhao H, Kalota A, Jin S, Gewirtz AM (2009) The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. Blood 113:505–516CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ruth G. Tatevossian
    • 1
  • Bo Tang
    • 1
  • James Dalton
    • 1
  • Tim Forshew
    • 2
  • Andrew R. Lawson
    • 2
  • Jing Ma
    • 3
  • Geoff Neale
    • 3
  • Sheila A. Shurtleff
    • 1
  • Simon Bailey
    • 4
  • Amar Gajjar
    • 5
  • Suzanne J. Baker
    • 6
  • Denise Sheer
    • 2
    Email author
  • David W. Ellison
    • 1
    Email author
  1. 1.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
  3. 3.Hartwell Center for Bioinformatics and BiotechnologySt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Sir James Spence Institute of Child HealthRoyal Victoria InfirmaryNewcastle upon TyneUK
  5. 5.Department of OncologySt Jude Children’s Research HospitalMemphisUSA
  6. 6.Department of Developmental NeurobiologySt Jude Children’s Research HospitalMemphisUSA

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