Elucidating the mechanisms by which spliceosomal gene LUC7L2 defects causes myeloid neoplasms

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09844
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Fukui
• Principal Investigator: Hosono Naoko 福井大学, 学術研究院医学系部門(附属病院部), 講師 (50509312)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨髄系腫瘍 / 7番染色体 / LUC7L2 / スプライシングの異常

Outline of Final Research Achievements

Deletions of the long arm of chromosome 7 are common karyotypic abnormalities in myeloid neoplasms and are associated with poor prognosis. LUC7L2, a putative U1 spliceosomal protein, is located in 7q34, which is deleted in 85% of -7/del7q patients. To clarify the role of LUC7L2 in myeloid neoplasms, we generated knocked down LUC7L2 in leukemic cell lines. Knockdown cells induced the formation of membrane blebs and adhere to each other. Expression analysis revealed increased expression of NOTCH3, AMIGO and ABLIM1 in knockdown cells. Skipping exon is most frequent alternative splicing event in knockdown cell, Mutually exclusive splicing event in HMGN1 were also seen in knockdown cell. Loss of function or low expression of LUC7L2 results in distinctly altered splicing patterns involving various kind of genes associated with cytoskeletal components, spliceosome, apoptosis or histone modification, and may collaborate to leukemogenesis.

Free Research Field

造血器腫瘍

Academic Significance and Societal Importance of the Research Achievements

骨髄系腫瘍でよくみられる異常であるLUC7L2の機能低下により、タンパク合成のステップの一つであるスプライシングの異常をきたし、その結果腫瘍の増殖に関わる多数の分子の発現が変化することが判明した。LUC7L2が介するこれらの分子の機能異常が、腫瘍化の原因および進展に関わることから、これらの分子を標的とした阻害物質の開発や、LUC7L2の機能を回復させる活性化物質の開発が、難治性骨髄系腫瘍の治療戦略になりうると期待される。