Homozygous Inactivation of the<i>NF1</i>Gene in Bone Marrow Cells from Children with Neurofibromatosis Type 1 and Malignant Myeloid Disorders

Side, Lucy; Taylor, Barry R.; Cayouette, Matthew C.; Conner, Edward; Thompson, Patrick; Luce, Michael C.; Shannon, Kevin

doi:10.1056/nejm199706123362404

Cited by 277 publications

(177 citation statements)

References 48 publications

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“…A recent study on NF-1 mutations in bone marrow cells supports a role for this gene in protection from JMML. 14,16,17 Somatic mutations in the G-CSF receptor were observed in some cases of severe congenital neutropenia, which can be associated with progression to MDS. 18,19 Hence, further investigation of MDS patients with a constitutional predisposition may help to discover genes involved in the pathogenesis of MDS.…”

Section: Discussionmentioning

confidence: 99%

Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan

et al. 2001

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We report a retrospective analysis of children with myelodysplastic syndrome (MDS) diagnosed between 1990 and 1997 in Japan. In total, 189 patients were enrolled: 122 cases of primary MDS (26 RA, 18 RAEB, 25 RAEBt, 53 CMML/JMML), 24 cases with constitutional predisposition to MDS, and 43 cases of therapy-related MDS (t-MDS). The frequency of pediatric MDS was estimated to be 7.7% of all leukemias. Cytogenetic abnormalities were observed in 41% of primary MDS and 90% of t-MDS cases. The 4-year survival rate, estimated by Kaplan-Meier analysis, for primary RA was 78.9%, while other types of MDS and JMML had rates lower than 40%, and t-MDS showed an even more unfavorable prognosis. In primary MDS, the survival rate of patients with cytogenetic abnormalities was significantly lower. Among prognostic variables by IPSS, only the cytogenetic pattern was useful for predicting outcome in childhood MDS. There was no apparent advantage to chemotherapy for RA, and the survival rate in patients with primary RA, JMML, or t-MDS receiving stem cell transplantation was significantly higher. More precise designs of our diagnostic and classification systems, as well as therapeutic trials in large-scale prospective studies, are necessary for further improvements in MDS outcome. Leukemia (2001) 15, 1713-1720.

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Section: Discussionmentioning

confidence: 99%

Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan

et al. 2001

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“…Furthermore, NF1 children have a higher risk to develop juvenile myelomonocytic leukemia with a potential progression to AML. Interestingly, in these cases, secondary mutations or somatic loss of the remained wild-type allele is observed, suggesting that NF1 acts as a tumor-suppressor gene according to Knudson's two-hit model [12,13]. In this context, many recent studies have investigated the incidence of NF1 deletion in AML but the frequency of this abnormality fluctuates according to screening methods used and size and heterogeneity of the cohorts analyzed [6,7,9,14].…”

Section: Introductionmentioning

confidence: 99%

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

et al. 2013

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On behalf of the French ALFA groupGermline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small~0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. Am. J.

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“…Scientific investigations have elucidated that approximately 10-25% of JMML patients acquire a somatic second hit to their remaining normal wild-type NF1 gene in their hematopoietic cells. 43,44 This complete lack of NF1 leads to a lack of neurofibromin, encoded by the NF1 gene, and subsequently hematopoietic cells cannot 'turn-off' Ras signaling. In essence, lack of neurofibromin due to NF1 gene loss is effectively the same as an activating RAS gene point mutation.…”

Section: Jmmlfpathogenesismentioning

confidence: 99%

“…38,39 At the molecular pathogenetic level a clinical association between JMML and the dominant familial cancer syndrome neurofibromatosis type 1 led astute investigators to the Ras signaling pathway. [40][41][42][43] Children with neurofibromatosis type 1 have a 500-fold increased predilection for developing JMML or other myeloid disorders. Interestingly, and for as yet unknown reasons, adults with neurofibromatosis type 1 outgrow this risk for myeloid diseases.…”

Section: Jmmlfpathogenesismentioning

confidence: 99%

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

2008

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Homozygous Inactivation of theNF1Gene in Bone Marrow Cells from Children with Neurofibromatosis Type 1 and Malignant Myeloid Disorders

Abstract: Both alleles of the NF1 gene are inactivated in leukemic cells in some patients with neurofibromatosis type 1. NF1 appears to function as a tumor-suppressor gene in immature myeloid cells.

Cited by 277 publications

References 48 publications

Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan

Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

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