Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup,British Journal of Haematology

当前位置： X-MOL 学术 › Br. J. Haematol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup
British Journal of Haematology ( IF 5.1 ) Pub Date : 2023-11-09 , DOI: 10.1111/bjh.19190
Senthilkumar Ramamoorthy _{1,

2} , Dirk Lebrecht ₁ , Denny Schanze ₃ , Ina Schanze ₃ , Ilse Wieland ₃ , Geoffroy Andrieux ₂ , Patrick Metzger ₂ , Maria Hess _{2,

4} , Michael H Albert ₅ , Arndt Borkhardt ₆ , Dorine Bresters ₇ , Jochen Buechner ₈ , Albert Catala ₉ , Valerie De Haas ₁₀ , Michael Dworzak _{11,

12} , Miriam Erlacher _{1,

13} , Henrik Hasle ₁₄ , Kirsi Jahnukainen ₁₅ , Franco Locatelli ₁₆ , Riccardo Masetti ₁₇ , Jan Stary ₁₈ , Dominik Turkiewicz ₁₉ , Luca Vinci ₁ , Marcin W Wlodarski ₁ , Ayami Yoshimi ₁ , Melanie Boerries _{2,

13} , Charlotte M Niemeyer _{1,

13} , Martin Zenker ₃ , Christian Flotho _{1,

13}

Affiliation

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Human Genetics, University of Magdeburg, Magdeburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Department of Pediatric Hematology and Oncology, Dr. v. Hauner Children's Hospital, University Hospital, LMU, Munich, Germany.
Department of Pediatric Oncology, Hematology and Immunology, University of Dusseldorf, Dusseldorf, Germany.
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
Department of Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
Diagnostic Laboratory/DCOG Laboratory, Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
St. Anna Children's Cancer Research Institute, Vienna, Austria.
Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Freiburg, Freiburg, Germany.
Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Catholic University of the Sacred Heart, Rome, Italy.
Pediatric Oncology and Hematology Unit "Lalla Seràgnoli", IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Pediatric Hematology/ Oncology, Charles University and Univ Hospital Motol, Prague, Czech Republic.
Department of Pediatric Oncology/Hematology, Skåne University Hospital, Lund, Sweden.

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.

中文翻译：

幼年型粒单核细胞白血病中 NF1 肿瘤抑制基因的双等位基因失活：驱动功能的遗传证据及其对诊断检查的影响

幼年型粒单核细胞白血病 (JMML) 的特点是基因变异导致 RAS 信号通路失调。患有 1 型神经纤维瘤病 (NF-1) 的儿童在种系中携带有缺陷的NF1等位基因，并且易患 JMML，这可能需要NF1野生型等位基因的体细胞失活。在这里，我们检查了 25 名 JMML 和 NF-1 患者的白血病细胞中的二次打击概念。 10 名 JMML/NF-1 患者表现出NF1功能丧失变异以及 17q 臂的单亲二体性。 5 例具有NF1微缺失和致病性NF1变异，9 例携带两种复合杂合NF1变异。我们还检查了 16 名没有 NF-1 临床症状且 JMML 相关驱动基因PTPN11 、 KRAS 、 NRAS或CBL (JMML-5neg) 没有变异的患者，并确定了 8 名患有 NF1 变异的患者。三名患者具有微缺失并伴有半合子NF1变异，三名患者具有复合杂合NF1变异，两名患者具有杂合NF1变异。此外，我们发现两组中继发ASXL1和/或SETBP1变异的发生率很高。我们的结论是，JMML/NF-1 的临床诊断可靠地表明了NF1驱动的 JMML 亚型，并且即使在没有 NF-1 临床证据的情况下，也应将仔细的NF1分析纳入 JMML 的基因检查中。

更新日期：2023-11-09

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南