title: The molecular genetic makeup of acute lymphoblastic leukemia.
abstract: Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.
authors.affiliation: Hematological Malignancies Program, St Jude Children’s Research Hospital, Memphis, TN 38105, USA. charles.mullighan@stjude.org
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
mesh_terms: D000328:Adult; D004171:Diploidy; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics; D007621:Karyotyping; D008957:Models, Genetic; D008967:Molecular Biology / Q000379:methods; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010770:Phosphotransferases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics; D012306:Risk; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; D010770:Phosphotransferases; D016044:Fusion Proteins, bcr-abl; D053613:Janus Kinase 1