title: [Alternative Splicing Detection as a Biomarker for Cancer Diagnosis: A Novel Progressive Mechanism of Acute Lymphoblastic Leukemia with Alternative Splicing as a Biomarker Candidate].
abstract: Alternative splicing is an important mechanism that links to transcription and contributes to protein diversity. Disturbed alternative splicing is frequently observed in cancers, but its precise mechanism remains largely unknown. FUSE-binding protein (FBP) -interacting repressor (FIR) is a transcriptional repressor of the c-myc gene. Previous studies indicated that a splice variant of FIR, FIRΔexon2, that lacks exon2 in the transcriptional repressor domain, was increased in colorectal cancers, hepatocellular carcinomas, and leukemia cells. Furthermore, FIRΔexon2 activated c-myc transcription by disabling wild-type FIR as a dominant-negative form of FIR. Recently, somatic mutations of the SF3B1 (SAP155) gene, a subunit of the SF3B spliceosome complex, were found in myelodysplastic leukemia. In this study, FIR heterozygous knockout (FIR(+/-)) was established as a dominant-negative model of FIR in the C57BL/6 mouse. FIR(+/-) mice showed an increased c-myc mRNA expression level, particularly in peripheral blood, although FIR(+/-) mice had no apparent pathogenic phenotype. Therefore, an increased c-myc mRNA expression level alone is not enough for leukemogenesis. Nevertheless, FIR(+/-)TP53(-/-) mice generated acute T-cell lymphoblastic leukemia (T-ALL) with increased organ and/or bone marrow invasion. In conclusion, alternative splicing of FIR, generating FIRΔexon2, contributes to not only colorectal carcinogenesis but also leukemogenesis independent of the c-Myc activation pathway. Finally, we will discuss our hypothesis that FIRΔexon2 interferes with FBW7, that FIRΔexon2 inhibits PP1 in the EGFR pathway, and that FIR haploinsufficiency is potentially associated with protein expression through transcriptional and post-transcriptional mechanisms.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.forename: Souhei
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishige
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Semba
authors.forename: Asako
authors.initials: A
authors.lastname: Kimura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kazami
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohyama
authors.forename: Sakae
authors.initials: S
authors.lastname: Itoga
authors.forename: Minako
authors.initials: M
authors.lastname: Beppu
authors.forename: Motoi
authors.initials: M
authors.lastname: Nishimura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics
chemical_list: D005819:Genetic Markers; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human