Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways.
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.
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany;
Stefan
S
Gröschel
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Mathijs A
MA
Sanders
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Remco
R
Hoogenboezem
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Annelieke
A
Zeilemaker
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Marije
M
Havermans
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Claudia
C
Erpelinck
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Eric M J
EM
Bindels
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; and Dutch Working Group on Hemato-Oncologic Genome Diagnostics, Rotterdam, The Netherlands.
H Berna
HB
Beverloo
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany;
Hartmut
H
Döhner
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Bob
B
Löwenberg
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany;
Konstanze
K
Döhner
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Ruud
R
Delwel
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Peter J M
PJ
Valk
D000483:Alleles; D002871:Chromosome Banding; D007446:Chromosome Inversion; D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D059472:Exome; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014178:Translocation, Genetic; D018631:ras Proteins / Q000378:metabolism*
D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins