The molecular mechanism that C/EBPa and Bcl11a induces AML development and progression

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17389
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: SUNAMI Yoshitaka 公益財団法人がん研究会, がん研究所 発がん研究部, 研究員 (50732864)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 急性骨髄性白血病 / Bcl11a / Asb2 / LSD1/HDAC阻害剤 / 骨髄生着

Outline of Final Research Achievements

C/EBPα and PU.1 are transcriptional factors that regulates myeloid differentiation in normal hematopoiesis, and these 2 factors act as tumor suppressors in AML. The pseudokinase Trib1 induces the degradation of C/EBPα p42 isoform, whereas transcriptional repressor Bcl11a suppresses the transcriptional activity of PU.1 by recruiting corepressors. We previously revealed that Bcl11a cooperates with Trib1 in the development of AML. In this project, we attempted to clarify that C/EBPα abnormality and Bcl11a-repressed PU.1 activity cooperatively induces AML development and progression. First, we found LSD1 and HDAC1/2 as corepressors that are recruited by Bcl11a in AML cells. Second, treatment of AML cells with LSD1/HDAC inhibitors resulted in the growth inhibition in a Bcl11a-expression dependent manners. Finally, we identified E3 ubiquitin ligase Asb2 as a novel Bcl11a target gene that promotes the engraftment of AML cells, subsequently induces AML development and progression.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

C/EBPαとPU.1は顆粒球系・単球系細胞の分化において競合的に働くとされており、これらの異常が協調してAMLを誘導するという先行研究はこれまでにない。また今回、同定したBcl11a新規標的遺伝子Asb2のAMLにおける役割については、これまでに十分な検討がされておらず、本研究成果の学術的意義は高い。
LSD1/HDAC阻害剤がAMLに有用であることが、複数の臨床試験により証明されており、Bcl11aはLSD1/HDAC阻害剤の治療効果予測因子となりうる。またBcl11a-Asb2経路を治療標的とすることでAMLの新規治療法開発につながる可能性があり、本研究で得られた成果は社会的意義も高い。