title: Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors.
abstract: In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. Furthermore, we show that most identified regions overlap with gene bodies of highly expressed genes and that induction of a myeloid lineage phenotype in transformed B cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia.
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK.
authors.forename: Bryant
authors.initials: B
authors.lastname: Boulianne
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robinson
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Molecular Pathology, Imperial College Healthcare NHS Trust, W12 0NN London, UK.
authors.forename: Philippa C
authors.initials: PC
authors.lastname: May
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Blighe
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Molecular Pathology, Imperial College Healthcare NHS Trust, W12 0NN London, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.affiliation: Department of Systems Biology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Pasadena, CA 91016, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK. Electronic address: n.feldhahn@imperial.ac.uk.
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D009857:Oncogenes / Q000235:genetics; D010641:Phenotype; D054448:Precursor Cells, B-Lymphoid / Q000473:pathology*; D014158:Transcription, Genetic / Q000235:genetics; D014170:Transformation, Genetic / Q000235:genetics*
keywords: B-cell precursors; DNA damage; clonal evolution; genomic instability; leukemia; oncogenic stress; transcription; transformation