Submitted June 12, 2007
Accepted December 16, 2007
Leukemia associated NF1 inactivation in pediatric T-ALL and AML patients 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, and Jules P.P. Meijerink*
Department of Pediatric Oncology/Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, Netherlands
Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
Dutch Childhood Oncology Group (DCOG), The Hague, Netherlands
AML-BFM Study Group, Hannover, Germany
German Co-operative study group for childhood acute lymphoblastic leukemia (COALL), Hamburg, Germany
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands
* Corresponding author; email: j.meijerink{at}erasmusmc.nl.
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. NF1 patients have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression towards acute myeloid leukemia (AML). In an oligo array-comparative genomic hybridization based screening of 103 pediatric T-cell acute lymphoblastic leukemia (T-ALL) and 71 MLL rearranged AML patients, a recurrent cryptic deletion, del(17)(q11.2), was identified in 3 T-ALL and 2 MLL rearranged AML patients. 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 towards the development of leukemia.
