Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways

• Published in: Blood 2015-01, Vol.125 (1), p.133-139
• Main Authors: Gröschel, Stefan, Sanders, Mathijs A., Hoogenboezem, Remco, Zeilemaker, Annelieke, Havermans, Marije, Erpelinck, Claudia, Bindels, EricM. J., Beverloo, H. Berna, Döhner, Hartmut, Löwenberg, Bob, Döhner, Konstanze, Delwel, Ruud, Valk, PeterJ. M.
• Format: Article
• Language: English
• Subjects: Alleles; Chromosome Banding; Chromosome Inversion; Chromosomes, Human, Pair 3; DNA Mutational Analysis; Epigenesis, Genetic; Exome; Gene Expression Profiling; Humans; Leukemia, Myeloid, Acute - genetics; Myelodysplastic Syndromes - genetics; Myeloid Neoplasia; ras Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Sequence Analysis, DNA; Sequence Analysis, RNA; Signal Transduction; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-07-591461

Myeloid malignancies bearing chromosomal inv(3)/t(3;3) abnormalities are among the most therapy-resistant leukemias. Deregulated expression of EVI1 is the molecular hallmark of this disease; however, the genome-wide spectrum of cooperating mutations in this disease subset has not been systematically elucidated. Here, we show that 98% of inv(3)/t(3;3) myeloid malignancies harbor mutations in genes activating RAS/receptor tyrosine kinase (RTK) signaling pathways. In addition, hemizygous mutations in GATA2, as well as heterozygous alterations in RUNX1, SF3B1, and genes encoding epigenetic modifiers, frequently co-occur with the inv(3)/t(3;3) aberration. Notably, neither mutational patterns nor gene expression profiles differ across inv(3)/t(3;3) acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome cases, suggesting recognition of inv(3)/t(3;3) myeloid malignancies as a single disease entity irrespective of blast count. The high incidence of activating RAS/RTK signaling mutations may provide a target for a rational treatment strategy in this high-risk patient group. •inv(3)/t(3;3) disease exhibits high rates of activated RAS/RTK signaling, epigenetic modifier, splice, and transcription factor mutations.•AML and MDS with inv(3)/t(3;3) display similar mutational and gene expression profiles and should be considered a single molecular entity.