Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Opatz, S; Polzer, H; Herold, T; Konstandin, NP; Ksienzyk, B; Zellmeier, E; Vosberg, S; Graf, A; Krebs, S; Blum, H; Hopfner, KP; Kakadia, PM; Schneider, S; Dufour, A; Braess, J; Sauerland, MC; Berdel, WE; Büchner, T; Woermann, BJ; Hiddemann, W; Spiekermann, K; Bohlander, SK; Greif, PA.
Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
Blood. 2013; 122(10): 1761-1769.
Doi: 10.1182/blood-2013-01-476473
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Vosberg Sebastian
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- Abstract:
- The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.
- Find related publications in this database (using NLM MeSH Indexing)
- Adolescent -
- Adult -
- Amino Acid Substitution -
- Apoptosis - drug effects
- Base Sequence -
- Benzothiazoles - pharmacology
- Cell Proliferation - drug effects
- Cell Transformation, Neoplastic - drug effects
- Cell Transformation, Neoplastic - pathology
- Core Binding Factor beta Subunit - genetics
- Cytokines - pharmacology
- DNA Mutational Analysis -
- Exome - genetics
- Female -
- Gene Expression Regulation, Leukemic - drug effects
- Gene Rearrangement -
- Humans -
- Leukemia - genetics
- Male -
- Middle Aged -
- Models, Molecular -
- Molecular Sequence Data -
- Mutation - genetics
- Oncogene Proteins, Fusion - genetics
- Phenylurea Compounds - pharmacology
- Protein Kinase Inhibitors - pharmacology
- Staurosporine - analogs & derivatives
- Staurosporine - pharmacology
- fms-Like Tyrosine Kinase 3 - chemistry
- fms-Like Tyrosine Kinase 3 - genetics