title: Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis.
abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. Patients with NF1 have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression toward acute myeloid leukemia (AML). In an oligo array comparative genomic hybridization-based screening of 103 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL) and 71 patients with MLL-rearranged AML, a recurrent cryptic deletion, del(17)(q11.2), was identified in 3 patients with T-ALL and 2 patients with MLL-rearranged AML. This deletion has previously been described as a microdeletion of the NF1 region in patients with NF1. However, our patients lacked clinical NF1 symptoms. Mutation analysis in 4 of these del(17)(q11.2)-positive patients revealed that mutations in the remaining NF1 allele were present in 3 patients, confirming its role as a tumor-suppressor gene in cancer. In addition, NF1 inactivation was confirmed at the RNA expression level in 3 patients tested. Since the NF1 protein is a negative regulator of the RAS pathway (RAS-GTPase activating protein), homozygous NF1 inactivation represent a novel type I mutation in pediatric MLL-rearranged AML and T-ALL with a predicted frequency that is less than 10%. NF1 inactivation may provide an additional proliferative signal toward the development of leukemia.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Balgobind
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Joan N R
authors.initials: JN
authors.lastname: Terlouw-Kromosoeto
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: van Wering
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Marry M
authors.initials: MM
authors.lastname: Van den Heuvel-Eibrink
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017253:Neurofibromatoses / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D025542:Neurofibromin 1; D012333:RNA, Messenger