Development of a novel mechanism of T-ALL and its clinical application for the diagnosis and treatment.

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26460667
• Research Institution: Chiba University
• Principal Investigator: 松下 一之 千葉大学, 医学部附属病院, 准教授 (90344994)
• Co-Investigator(Kenkyū-buntansha): 野村 文夫 千葉大学, 医学部附属病院, 特任教授 (80164739) ; 星野 忠次 千葉大学, 大学院薬学研究院, 准教授 (90257220)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 急性リンパ性白血病 / 癌糖代謝 / c-myc / スプライシング / 質量分析

Outline of Annual Research Achievements

The switch of pyruvate kinase (PK) M1 and PKM2 is pivotal for glucose metabolism in cancers. The PKM1/M2 shift is controlled by the alternative splicing of two mutually exclusive exons in the PKM gene. PKM1 is expressed in differentiated tissues, whereas PKM2 is expressed in cancer tissues. FUSE-binding protein (FBP)-interacting repressor (FIR) is a transcriptional repressor of the c-myc gene. Mice was prepared and diagnosed as thymic lymphoma and/or T-call type acute lymphoblastic leukemia (T-ALL), depending on circulating tumor cells/bone marrow invasion revealed by flow cytometry analysis. This study revealed that haplodeficiency of FIR significantly contributed to the splicing of PKM1 to PKM2 in mice thymic lymphoma using six-plex tandem mass tag (TMT) quantitative proteomic analysis in this mice model. TMT revealed 648 proteins that were up- or downregulated in mice thymic lymphoma tissues. These proteins included transcription factors and proteins involved in DNA damage repair, DNA replication, T-cell activation/proliferation, apoptosis, etc. Among them, PKM2 protein, but not PKM1, was upregulated in the thymic lymphoma as well as T-ALL. FIR knockdown by siRNA suppressed hnRNPA1 expression in HeLa cells. These results indicated that FIR haplodeficiency contributes the alternative splicing of PKM1 to PKM2 by partly inhibiting hnRNPA1 expression in the thymic lymphoma cells prior to T-ALL. Taken together, our findings suggest that FIR and its related spliceosomes are potential therapeutic targets for cancers, including T-ALL.

Research Products

• [Journal Article] Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients. (2016)
  • Author(s): 94.Kobayashi S, Hoshino T, Hiwasa T, Satoh M, Rahmutulla B, Tsuchida S, Komukai Y, Tanaka T, Matsubara H, Shimada H, Nomura F, Matsushita K.
  • Journal Title: Oncotarget Volume: 7 Pages: 82493-82503
  • DOI: 10.18632/oncotarget.12696
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development and validation of the simultaneous measurement of four vitamin D metabolites in serum by LC-MS/MS for clinical laboratory applications. (2016)
  • Author(s): 92.Satoh M, Ishige T, Ogawa S, Nishimura M, Matsushita K, Higashi T, Nomura F.
  • Journal Title: Anal Bioanal Chem. Volume: 27 Pages: 7617-7627
  • DOI: 10.1007/s00216-016-9821-4
  • Peer Reviewed
• [Presentation] Alternative splicing as biomarkers for DNA damage response: A novel mechanism of cancer progression through a single-nucleotides binding/multi-functional protein, FIR. (2016)
  • Author(s): Matsushita K. Rahmutulla B. Kitamura K, Beppu M. Nishimura M, Satoh M and Nomura F.
  • Organizer: ICHG2016 [The 13th International Congress of Human Genetics
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2016-04-03 – 2016-04-07
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 癌の予防剤および/または治療剤 (2015)
  • Inventor(s): 松下一之
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: ６０５７４０８
  • Filing Date: 2015-03-05
  • Acquisition Date: 2016-12-16