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

(2008) BLOOD. 111(8). p.4322-4328
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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.
Keywords
NUCLEOTIDE POLYMORPHISM ANALYSIS, ACUTE LYMPHOBLASTIC-LEUKEMIA, UNIPARENTAL DISOMY, SOMATIC RECOMBINATION, ACUTE MYELOID-LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, MOLECULAR-GENETICS, TYPE-1, ACTIVATION, CHILDREN

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Chicago
Balgobind, Brian V, Pieter Van Vlierberghe, Ans MW van den Ouweland, H Berna Beverloo, Joan NR Terlouw-Kromosoeto, Elisabeth R van Wering, Dirk Reinhardt, et al. 2008. “Leukemia-associated NF1 Inactivation in Patients with Pediatric T-ALL and AML Lacking Evidence for Neurofibromatosis.” Blood 111 (8): 4322–4328.
APA
Balgobind, B. V., Van Vlierberghe, P., van den Ouweland, A. M., Beverloo, H. B., Terlouw-Kromosoeto, J. N., van Wering, E. R., Reinhardt, D., et al. (2008). Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. BLOOD, 111(8), 4322–4328.
Vancouver
1.
Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo HB, Terlouw-Kromosoeto JN, van Wering ER, et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. BLOOD. 2008;111(8):4322–8.
MLA
Balgobind, Brian V et al. “Leukemia-associated NF1 Inactivation in Patients with Pediatric T-ALL and AML Lacking Evidence for Neurofibromatosis.” BLOOD 111.8 (2008): 4322–4328. Print.
@article{5646968,
  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.},
  author       = {Balgobind, Brian V and Van Vlierberghe, Pieter and van den Ouweland, Ans MW and Beverloo, H Berna and Terlouw-Kromosoeto, Joan NR and van Wering, Elisabeth R and Reinhardt, Dirk and Horstmann, Martin and Kaspers, Gertjan JL and Pieters, Rob and Zwaan, C Michel and Van den Heuvel-Eibrink, Marry M and Meijerink, Jules PP},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keywords     = {NUCLEOTIDE POLYMORPHISM ANALYSIS,ACUTE LYMPHOBLASTIC-LEUKEMIA,UNIPARENTAL DISOMY,SOMATIC RECOMBINATION,ACUTE MYELOID-LEUKEMIA,JUVENILE MYELOMONOCYTIC LEUKEMIA,MOLECULAR-GENETICS,TYPE-1,ACTIVATION,CHILDREN},
  language     = {eng},
  number       = {8},
  pages        = {4322--4328},
  title        = {Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis},
  url          = {http://dx.doi.org/10.1182/blood-2007-06-095075},
  volume       = {111},
  year         = {2008},
}

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