title: Genetic lesions in a preleukemic aplasia phase in a child with acute lymphoblastic leukemia.
abstract: In a small fraction ( approximately 2%) of cases of childhood acute lymphoblastic leukemia (ALL) clinical presentation of leukemia is preceded, some 2-9 months earlier, by a transient, remitting phase of nonclassical aplastic anemia, usually in connection with infection. The potential "preleukemic" nature of this prodromal phase has not been fully explored. We have retrospectively analyzed the blood and bone marrow of a child who presented with aplastic anemia 9 months before the development of ETV6-RUNX1 fusion gene positive ALL. High resolution SNP genotyping arrays identified 11 regions of loss of heterozygosity, with and without concurrent copy number changes, at the presentation of ALL. In all cases of copy number change, the deletion or gain identified by single nucleotide polymorphism (SNP) analysis was confirmed in the ALL blasts by FISH. Retrospective analysis of aplastic phase bone marrow showed that the ETV6-RUNX1 fusion was present along with all of the additional genetic changes assessed, albeit subclonal to ETV6-RUNX1. These data identify for the first time the leukemic genotype of an aplasia preceding clinical ALL and indicate that multiple secondary genetic abnormalities can contribute to a dominant subclone several months before a diagnosis of ALL. These data have implications for the biology of ALL and for management of similar patients.
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey, UK.
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Horsley
authors.forename: Susan
authors.initials: S
authors.lastname: Colman
authors.forename: Mark
authors.initials: M
authors.lastname: McKinley
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Bateman
authors.forename: Meriel
authors.initials: M
authors.lastname: Jenney
authors.forename: Tracy
authors.initials: T
authors.lastname: Chaplin
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.forename: Lyndal
authors.initials: L
authors.lastname: Kearney
mesh_terms: D000741:Anemia, Aplastic / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D046228:Microarray Analysis; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011289:Preleukemia / Q000235:genetics* / Q000473:pathology; D012189:Retrospective Studies; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein