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Mosaiktrisomie 8p11.21q11.21 als Prädisposition für myeloische Leukämien

Mosaic trisomy 8p11.21q11.21 predisposing to myeloid leukemia

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medizinische genetik

Zusammenfassung

Bei der juvenilen myelomonozytären Leukämie (JMML) handelt es sich um eine myeloproliferative Erkrankung der frühen Kindheit. Bei vielen Patienten lassen sich zugrunde liegende somatische, aber auch konstitutionelle Mutationen in NRAS, KRAS, PTPN11, NF1 und CBL nachweisen. Zur Identifizierung submikroskopischer Veränderungen, die für die leukämische Transformation von Bedeutung sein können, wurden 20 JMML-Proben mittels hochauflösender Oligo-Microarray-basierter komparativer genomischer Hybridisierung (aCGH) untersucht. Bei 2 von 10 Patienten mit submikroskopischen Aberrationen konnte ein nahezu identischer Zugewinn von Chromosom 8 gezeigt werden, der sich in weiteren Untersuchungen als konstitutionelles Mosaik darstellte. Eine Übersicht von 27 Patienten mit einem konstitutionellen Trisomie-8-Mosaik (cT8M) und maligner Neoplasie zeigte, dass es sich meist um myeloische Neoplasien, auch JMML, handelt. Durch unsere Untersuchungen konnte die kritische Region auf Chromosom 8, deren Loci mutmaßlich an der Leukämieentstehung und/oder Progression beteiligt sein können, dramatisch reduziert werden: 8p11.21q11.21. Es bleibt zu klären in welcher Form das partielle Trisomie-8-Mosaik an der Leukämieentstehung beteiligt ist und in welcher Weise dies für verschiedenen Mutationssubtypen der JMML eine Rolle spielt.

Abstract

Juvenile myelomonocytic leukemia (JMML) is a unique myeloproliferative disorder of early childhood in which mutations in NRAS, KRAS, PTPN11, NF1 and CBL are frequently found. Using high-resolution oligo array-based comparative genomic hybridization (aCGH), 20 JMML samples were investigated for submicroscopic genomic copy number alterations. Besides known cytogenetic aberrations, ten samples displayed additional submicroscopic alterations. Interestingly, an almost identical gain of chromosome 8 was identified in two patients. Subsequently, fluorescence in situ hybridization indicated a constitutional partial trisomy 8 mosaic (cT8M) in both patients. A survey on 27 cT8M patients with reported malignancies showed a predominance of myeloid malignancies including JMML. Our results dramatically reduce the critical region on chromosome 8 to 8p11.21q11.21. To determine how constitutional partial trisomy 8 mosaicisms may contribute to leukemogenesis in different mutational subtypes of JMML and other myeloid malignancies, further investigations are required.

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Danksagung

Wir danken allen an der Studie beteiligten Patienten und Kollegen. Die Arbeit von Tim Ripperger wurde zum Teil durch ein Stipendium der Hannover Biomedical Research School, PhD Programm Molecular Medicine finanziert. Abschließend danken wir Gillian Teicke für die kritische Durchsicht des Manuskriptes und dem British Journal of Haematology (Wiley-Blackwell), dass wir die Abbildung aus der Originalpublikation des Artikels [44] weitestgehend identisch verwenden konnten.

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  1. Institut für Zell- und Molekularpathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland

    T. Ripperger, B. Schlegelberger &  D. Steinemann

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  1. T. Ripperger
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  2. B. Schlegelberger
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Ripperger, T., Schlegelberger, B. & Steinemann, D. Mosaiktrisomie 8p11.21q11.21 als Prädisposition für myeloische Leukämien. medgen 24, 33–39 (2012). https://doi.org/10.1007/s11825-012-0316-1

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