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

TY - JOUR

T1 - Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis.

AU - Balgobind, [Unbekannt]

AU - Brian, V

AU - Vlierberghe, Van

AU - Pieter, [Unbekannt]

AU - van Den, Ouweland

AU - Ans, M W

AU - Beverloo, [Unbekannt]

AU - Berna, H

AU - Terlouw-Kromosoeto, [Unbekannt]

AU - Joan, N R

AU - Wering, van

AU - Elisabeth, R

AU - Reinhardt, [Unbekannt]

AU - Dirk, [Unbekannt]

AU - Horstmann, Martin

AU - Martin, [Unbekannt]

AU - Kaspers, [Unbekannt]

AU - Gertjan, J L

AU - Pieters, [Unbekannt]

AU - Rob, [Unbekannt]

AU - Zwaan, [Unbekannt]

AU - Michel, C

AU - Heuvel-Eibrink, Van Den

AU - Marry, M

AU - Meijerink, [Unbekannt]

AU - Jules, P P

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 111

SP - 4322

EP - 4328

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 8

M1 - 8

ER -