title: Crizotinib resistance in acute myeloid leukemia with inv(2)(p23q13)/RAN binding protein 2 (RANBP2) anaplastic lymphoma kinase (ALK) fusion and monosomy 7.
abstract: This is the first report on the development of a p.G1269A mutation within the kinase domain (KD) of ALK after crizotinib treatment in RANBP2-ALK acute myeloid leukemia (AML). An elderly woman with AML with an inv(2)(p23q13)/RANBP2-ALK and monosomy 7 was treated with crizotinib. After a short-term hematological response and the restoration of normal hematopoiesis, she experienced a relapse of AML. Fluorescence in situ hybridization using the ALK break-apart probe confirmed the inv(2)(p23q13), while G-banded karyotyping revealed the deletion of a segment of the short arm of chromosome 1 [del(1)(p13p22)] after crizotinib therapy. The ALK gene carried a heterozygous mutation at the nucleotide position g.716751G>C within exon 25, causing the p.G1269A amino acid substitution within the ALK-KD. Reverse transcriptase PCR revealed that the mutated ALK allele was selectively transcribed and the mutation occurred in the ALK allele rearranged with RANBP2. As both the del(1)(p13p22) at the cytogenetic level and p.G1269A at the nucleotide level newly appeared after crizotinib treatment, it is likely that they were secondarily acquired alterations involved in crizotinib resistance. Although secondary genetic abnormalities in ALK are most frequently described in non-small cell lung cancers harboring an ALK alteration, this report suggests that an ALK-KD mutation can occur independently of the tumor cell type or fusion partner after crizotinib treatment.
authors.affiliation: Tenri Institute of Medical Research, Tenri Hospital, Nara, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Takeoka
authors.affiliation: Tenri Institute of Medical Research, Tenri Hospital, Nara, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Okumura
authors.affiliation: Department of Hematology, Tenri Hospital, Nara, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Maesako
authors.affiliation: Department of Hematology, Tenri Hospital, Nara, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasaka
authors.affiliation: Tenri Institute of Medical Research, Tenri Hospital, Nara, Japan; Department of Hematology, Tenri Hospital, Nara, Japan. Electronic address: hohno@tenriyorozu.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohno
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002872:Chromosome Deletion; D007446:Chromosome Inversion; D002889:Chromosomes, Human, Pair 2; D002897:Chromosomes, Human, Pair 7; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics
chemical_list: D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C094493:ran-binding protein 2; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: AML with inv(2)(p23q13)/RANBP2-ALK and monosomy 7; Crizotinib resistance; del(1)(p13p22); p.G1269A mutation