Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia : Genetic evidence of driver function and implications for diagnostic workup
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd..
Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:204 |
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| Enthalten in: |
British journal of haematology - 204(2024), 2 vom: 05. Feb., Seite 595-605 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ramamoorthy, Senthilkumar [VerfasserIn] |
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| Links: |
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| Themen: |
JMML |
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| Anmerkungen: |
Date Completed 08.02.2024 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bjh.19190 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Ramamoorthy, Senthilkumar |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia |b Genetic evidence of driver function and implications for diagnostic workup |
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| 500 | |a Date Revised 05.03.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. | ||
| 520 | |a Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Lebrecht, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Schanze, Denny |e verfasserin |4 aut | |
| 700 | 1 | |a Schanze, Ina |e verfasserin |4 aut | |
| 700 | 1 | |a Wieland, Ilse |e verfasserin |4 aut | |
| 700 | 1 | |a Andrieux, Geoffroy |e verfasserin |4 aut | |
| 700 | 1 | |a Metzger, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Hess, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Albert, Michael H |e verfasserin |4 aut | |
| 700 | 1 | |a Borkhardt, Arndt |e verfasserin |4 aut | |
| 700 | 1 | |a Bresters, Dorine |e verfasserin |4 aut | |
| 700 | 1 | |a Buechner, Jochen |e verfasserin |4 aut | |
| 700 | 1 | |a Catala, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a De Haas, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Dworzak, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Erlacher, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Hasle, Henrik |e verfasserin |4 aut | |
| 700 | 1 | |a Jahnukainen, Kirsi |e verfasserin |4 aut | |
| 700 | 1 | |a Locatelli, Franco |e verfasserin |4 aut | |
| 700 | 1 | |a Masetti, Riccardo |e verfasserin |4 aut | |
| 700 | 1 | |a Stary, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Turkiewicz, Dominik |e verfasserin |4 aut | |
| 700 | 1 | |a Vinci, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Wlodarski, Marcin W |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshimi, Ayami |e verfasserin |4 aut | |
| 700 | 1 | |a Boerries, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Niemeyer, Charlotte M |e verfasserin |4 aut | |
| 700 | 1 | |a Zenker, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Flotho, Christian |e verfasserin |4 aut | |
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