Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1

Maris, John M.; Wiersma, Susan R.; Mahgoub, Nidal; Thompson, Patrick; Geyer, Russell; Hurwitz, Carole G.�H.; Lange, Beverly J.; Shannon, Kevin

doi:10.1002/(sici)1097-0142(19970401)79:7<1438::aid-cncr22>3.3.co;2-a

Cited by 36 publications

(52 citation statements)

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“…Children with neurofibromatosis type 1 are at increased risk of developing both primary and treatment-related malignancies, including t-MDS/t-AML. 16,17 Indeed, treatment of Nf1 knockout mice with radiotherapy and alkylating agents lead to a significant increase in myeloid neoplasms. 18,19 We recently described germline mutations in the C-RAF proto-oncogene that might predispose their carriers to the primary tumor, as well as to t-AML.…”

Section: Loss Of Rkip In T-aml a Zebisch Et Almentioning

confidence: 99%

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

et al. 2009

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We recently described oncogenic and anti-apoptotic C-RAF germline mutations in patients with therapy-related acute myeloid leukemia (t-AML). Activation of the RAF effector ERK was restricted to transformed cells, suggesting the requirement for cooperating events in leukemogenesis. Western blot analysis of blast cells from patients with C-RAF germline mutations revealed loss of the tumor and metastasis suppressor RAF kinase inhibitor protein (RKIP). Immunohistochemistry of the patients' primary tumors revealed normal RKIP expression levels, indicating that the loss of RKIP is a somatic, t-AMLspecific event. In focus formation assays, the oncogenic potential of human mutant C-RAF was strongly influenced by expression levels of RKIP. Although the number of colonies formed by C-RAF S427G was significantly increased by RKIP silencing, the opposite was observed after RKIP overexpression. These results show that the loss of RKIP is a functional somatic event in carriers of C-RAF germline mutations, which contributes to the development of t-AML.

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Section: Loss Of Rkip In T-aml a Zebisch Et Almentioning

confidence: 99%

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

et al. 2009

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“…This is particularly relevant in persons with NF1 as retrospective clinical data suggest that treatment with genotoxins for a primary cancer markedly ncreases the risk of common SMNs such as myeloid leukemia and soft tissue sarcoma (29,30) Based on these clinical observations and on the lack of robust animal models of SMN, the Shannon lab administered either the alkylating agent cyclophosphamide (CY), a single dose of total body irradiation (TBI), or both genotoxins to heterozygous Nf1 mutant mice (Nf1 +/-) (7, 9). When delivered alone or in combination with cyclophosphamide, TBI induced a spectrum of SMNs in Nf1 +/-mice that included myeloid malignancies, soft tissue sarcomas, and breast carcinomas.…”

Section: G12dmentioning

confidence: 99%

Preclinical Mouse Models of Neurofibromatosis

Shannon¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTThis report describes the past four years of research performed by a Consortium of investigators who were continuously funded by this Program since 1999 to develop, characterize, and utilize strains of mice that accurately model tumors found in persons with NF1 and NF2. This Consortium has generated many novel models of NF1 and NF2-associated tumors and has exploited these strains to investigate biologic and preclinical questions. The investigators have collaborated closely and have extensively shared expertise and reagents with each other and with NF researchers around the world. These mouse strains developed through this effort are a cornerstone of NF research and are instrumental to an effort by the Children's Tumor Foundation to organize and support a preclinical network for testing therapeutics that might benefit persons with NF1 and NF2 disease. SUBJECT TERMS INTRODUCTIONBenign and malignant tumors are a major cause of morbidity and mortality in individuals with NF1 and NF2. The NF1 and NF2 genes function as tumor suppressors in humans and mice. Although a great deal has been learned about the genetics, biochemistry, and cell biology of NF1 and NF2-associated tumors, it has proven difficult to translate these advances into new treatments. Accurate, well-characterized mouse models of NF-associated tumors are invaluable resources for achieving the long-term goal of bringing improved treatments to NF patients. The overall purpose of this consortium, which is now ending after 10 years, has been to develop such models that would serve as permanent resources for the scientific community. These efforts were timely for a number of reasons.First, advances in gene targeting technologies in the late 1990s made it feasible to introduce many types of alterations into the mouse germline. Indeed, investigators who pioneered this general strategy were awarded the Nobel Prize in Medicine in 2007. The members of this research consortium developed the initial strains of Nf1 and Nf2 mutant mice, which provided major insights into a number of the complications seen in human NF1 and NF2 patients. Through this consortium effort, we engineered conditional mutant alleles of both Nf1 and Nf2 and in used these novel strains to create tractable new models for biologic and preclinical studies. Second, investigating cells from these Nf1 and Nf2 mutant mice has provided numerous fundamental insights that are directly relevant to understanding deregulated growth in NF1 and NF2-deficient human cells. Genetic analys...

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“…Neurofibromatosis type 1 (NF1) is an autosomal, dominant Review ª 2007 The Authors disorder in which NF1 mutations result in deregulated RAS signalling. Children with NF1 have been shown to be susceptible to the development of secondary malignant myeloid disorders following genotoxic treatment (Maris et al, 1997). In addition, Mahgoub et al (1999) demonstrated that heterozygote NF1 knockout mice were susceptible to t-AML following treatment with alkylating agents.…”

Section: Genetic Mutations Predisposing To T-amlmentioning

confidence: 99%

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

Seedhouse

Russell

2007

Br J Haematol

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SummaryTreatment-related acute myeloid leukaemia (t-AML) is a devastating complication following exposure to the cytotoxic and genotoxic agents used to treat a primary malignancy. Whilst the incidence of t-AML is rising, it still only occurs in a minority of patients who have received chemotherapy and/or radiotherapy treatment and hence it is important to identify factors that may confer susceptibility to the development of the condition. This paper reviews the literature and discusses the advances and limitations in our understanding of susceptibility factors to t-AML. In particular, it concentrates upon genetic polymorphisms in detoxification genes and in genes belonging to the major DNA repair pathways. This review also considers more novel susceptibility factors, such as those proposed to determine stem cell number. Increased understanding of t-AML susceptibility may enable steps to be taken to prevent its development and increase the effectiveness of treatment of the disease.

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Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1

Abstract: Children with NF1 are susceptible to the development of malignant myeloid disorders both as a primary event and as an SMN. Additional molecular genetic analysis is necessary to determine if the NF1 gene is inactivated by somatic mutation in these secondary leukemias.

Cited by 36 publications

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Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

Preclinical Mouse Models of Neurofibromatosis

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

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