Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis

Brian V. Balgobind, Pieter Van Vlierberghe, Ans M.W. Van Den Ouweland, H. Berna Beverloo, Joan N.R. Terlouw-Kromosoeto, Elisabeth R. Van Wering, Dirk Reinhardt, Martin Horstmann, Gertjan J.L. Kaspers, Rob Pieters, C. Michel Zwaan, Marry M. Van Den Heuvel-Eibrink, Jules P.P. Meijerink

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105 Citaten (Scopus)

Samenvatting

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 R AS 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.

Originele taal-2Engels
Pagina's (van-tot)4322-4328
Aantal pagina's7
TijdschriftBlood
Volume111
Nummer van het tijdschrift8
DOI's
StatusGepubliceerd - 15 apr. 2008
Extern gepubliceerdJa

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