title: Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies.
abstract: Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially "druggable". The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe.
authors.affiliation: Nemours Center for Cancer and Blood Disorders, Nemours/A. I. duPont Hospital for Children, Wilmington, DE; and.
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004314:Down Syndrome / Q000150:complications / Q000628:therapy; D044127:Epigenesis, Genetic; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D008495:Medical Oncology / Q000379:methods; D062346:Molecular Medicine / Q000379:methods; D009154:Mutation; D010087:Oxides / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use; D018631:ras Proteins / Q000378:metabolism
chemical_list: D001152:Arsenicals; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D010087:Oxides; D014212:Tretinoin; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins; D000077237:Arsenic Trioxide