title: The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia.
abstract: Over 90% of infants (< 1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia.
authors.affiliation: Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sherborne
authors.forename: Yussanne P
authors.initials: YP
authors.lastname: Ma
authors.forename: Michela
authors.initials: M
authors.lastname: Bardini
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Amy
authors.initials: A
authors.lastname: Lloyd
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.forename: Mel F
authors.initials: MF
authors.lastname: Greaves
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein