title: Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.
abstract: Chronic myeloproliferative disorders with rearrangements of the platelet-derived growth factor receptor A (PDGFRA) gene at chromosome band 4q12 have shown excellent responses to targeted therapy with imatinib. Here we report a female patient who presented with advanced phase of a chronic eosinophilic leukemia. Cytogenetic analysis revealed an ins(9;4)(q33;q12q25) in 5 of 21 metaphases. FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. A novel mRNA in-frame fusion between exon 13 of the CDK5 regulatory subunit associated protein 2 (CDK5RAP2) gene, a 40-bp insert that was partially derived from an inverted sequence stretch of PDGFRA intron 9, and a truncated PDGFRA exon 12 was identified by 5'-RACE-PCR. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. The predicted CDK5RAP2-PDGFRA protein consists of 1,003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerization domains of CDK5RAP2. Despite achieving complete cytogenetic and molecular remission on imatinib, the patient relapsed with imatinib-resistant acute myeloid leukemia that was characterized by a normal karyotype, absence of detectable CDK5RAP2-PDGFRA mRNA, and a newly acquired G12D NRAS mutation.
authors.affiliation: III. Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.forename: Claire
authors.initials: C
authors.lastname: Curtis
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Beate
authors.initials: B
authors.lastname: Schultheis
authors.forename: Georgia
authors.initials: G
authors.lastname: Metzgeroth
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Eva
authors.initials: E
authors.lastname: Lengfelder
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D001549:Benzamides; D018797:Cell Cycle Proteins; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy* / Q000235:genetics*; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha