Title: The Role of Trib1/Cop1 axis in Acute Myeloid Leukemia

 

Speaker: Yoshitaka Sunami, M.D, Ph.D.

Associate Professor, Department of Experimental Pathology, IMS, Tokyo Medical University

 

 

Cop1/RFWD2 is a ubiquitin E3 ligase conserved from plants to mammals. Our laboratory previously identified the pseudokinase Trib1 as a partner gene of Hoxa9 and Meis1 in driving myeloid leukemogenesis. We also identified the C2H2 zinc finger protein Bcl11a/Evi9 as a cooperative partner of Trib1, which promotes acute myeloid leukemia (AML) progression by suppressing PU.1 transcriptional activity. Overexpression of Trib1 induces AML by promoting the degradation of C/EBPα p42, a key transcription factor for granulocytic differentiation, through its interaction with Cop1.

To investigate the roles of Cop1 in AML, we generated Cop1 conditional knockout (cKO) mice and established AML cell lines from their bone marrow cells. Cop1 cKO induced rapid growth arrest and granulocytic differentiation, accompanied by a transient rise in C/EBPα p42 in a Trib1-dependent manner. Trib1 induction increased Cebpa mRNA expression, and Cop1 KO further increased C/EBPα p42 protein by inhibiting its degradation, resulting in suppression of AML cell proliferation. These findings suggest that while Trib1 contributes to AML progression, Trib1/Cop1-mediated C/EBPα p42 degradation leads to a vulnerability in AML cells by upregulating Cebpa transcription. We also found that Trib1 undergoes self-degradation by the Cop1 degradosome. These results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity.

In this seminar, I will also discuss the roles of Trib1/Cop1 axis in normal hematopoiesis and its potential as a novel therapeutic target in AML.

 

 

References

Sunami Y, Yoshino S, Yamazaki Y, Iwamoto T, Nakamura T. Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML. Leukemia. 2024 Dec;38(12):2585-2597.

 

Sunami Y, Yokoyama T, Yoshino S, Takahara T, Yamazaki Y, Harada H, Nakamura T. BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes. Blood Adv. 2022 Mar 22;6(6):1827-1843.

 

Yoshino S, Yokoyama T, Sunami Y, Takahara T, Nakamura A, Yamazaki Y, Tsutsumi S, Aburatani H, Nakamura T. Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9. Blood. 2021 Jan 7;137(1):75-88.