title: Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia.
abstract: Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39-year-old woman at MDS/MPN-U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non-silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN-U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden.
authors.forename: Axel
authors.initials: A
authors.lastname: Hyrenius-Wittsten
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Sturesson
authors.affiliation: Department of Clinical Genetics, Lund University, Skane University Hospital, Lund, Sweden.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Bidgoli
authors.affiliation: Department of Clinical Genetics, Lund University, Skane University Hospital, Lund, Sweden.
authors.forename: Tord
authors.initials: T
authors.lastname: Jonson
authors.affiliation: Department of Pathology, Lund University, Skane University Hospital, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine Lund, Lund Stem Cell Center, Lund University, Lund, Sweden.|Department of Hematology, Lund University, Skane University Hospital, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Scheding
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden. Anna.Andersson@med.lu.se.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000069286:Bortezomib / Q000008:administration & dosage; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D018450:Disease Progression; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020440:Gene Duplication; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage
chemical_list: C000717967:DNMT3A protein, human; C497422:KMT2A protein, human; D008565:Membrane Proteins; D011728:Pyridones; D011744:Pyrimidinones; D051788:Myeloid-Lymphoid Leukemia Protein; C560077:trametinib; D000069286:Bortezomib; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human