The clinical mutatome of core binding factor leukemia.

Autor: Opatz S; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Bamopoulos SA; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Metzeler KH; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Herold T; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Ksienzyk B; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Bräundl K; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Tschuri S; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Vosberg S; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Konstandin NP; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Wang C; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Hartmann L; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Graf A; Laboratory for Functional Genome Analysis at the Gene Center, LMU Munich, Munich, Germany., Krebs S; Laboratory for Functional Genome Analysis at the Gene Center, LMU Munich, Munich, Germany., Blum H; Laboratory for Functional Genome Analysis at the Gene Center, LMU Munich, Munich, Germany., Schneider S; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Institute of Human Genetics, University Hospital, LMU Munich, Munich, Germany., Thiede C; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Middeke JM; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Stölzel F; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Röllig C; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Schetelig J; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Ehninger G; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Dresden, Germany., Krämer A; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Braess J; Oncology and Hematology, St. John of God Hospital, Regensburg, Germany., Görlich D; Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany., Sauerland MC; Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany., Berdel WE; Department of Medicine A, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany., Wörmann BJ; Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, Berlin, Germany., Hiddemann W; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Spiekermann K; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Bohlander SK; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand., Greif PA; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. pgreif@med.uni-muenchen.de.; Experimental Leukemia & Lymphoma Research, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. pgreif@med.uni-muenchen.de.; German Cancer Consortium (DKTK), Heidelberg, Germany. pgreif@med.uni-muenchen.de.; German Cancer Research Center (DKFZ), Heidelberg, Germany. pgreif@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2020 Jun; Vol. 34 (6), pp. 1553-1562. Date of Electronic Publication: 2020 Jan 02.
DOI: 10.1038/s41375-019-0697-0
Abstrakt: The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.
Databáze: MEDLINE
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