title: Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.
abstract: Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: T
authors.identifier: 0000-0002-5727-4470
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kiyokawa
authors.affiliation: Department of Pediatrics, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Imai
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohki
authors.affiliation: National Hospital Organization Nagoya Medical Center, Clinical Research Center, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Department of Hematology and Oncology, Hyogo Prefectural Children's Hospital, Kobe, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ishimaru
authors.affiliation: Department of Pediatrics, Mie University, Tsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Deguchi
authors.affiliation: Department of Pediatrics, Osaka University, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hashii
authors.affiliation: Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shimomura
authors.affiliation: Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hori
authors.affiliation: Division of Pediatric Hematology/Oncology, Ibaraki Children's Hospital, Mito, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.affiliation: Division of Hemato-Oncology and Regenerative Medicine, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Ogawa
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taki
authors.affiliation: Department of Pediatrics, St Luke's International Hospital, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Fukushima Medical School, Fukushima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kikuta
authors.affiliation: Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Department of Pediatrics, Toho University, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ohara
authors.affiliation: Department of Pediatrics, Nakadori General Hospital, Akita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Ishii
authors.affiliation: Department of Pediatrics, School of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shimada
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007223:Infant; D053614:Janus Kinase 2 / Q000235:genetics; D007564:Japan; D008297:Male; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; D015514:Oncogene Proteins, Fusion; D051740:Ikaros Transcription Factor; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2