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Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells

 Hyunsoo Cho  ;  Ji Eun Jang  ;  Ju-In Eom  ;  Hoi-Kyung Jeung  ;  Haerim Chung  ;  Jin Seok Kim  ;  June-Won Cheong  ;  Yoo Hong Min 
Journal Title
Issue Date
Acute myeloid leukaemia ; Apoptosis ; Arsenic trioxide ; Venetoclax
Background: The evasion of apoptosis through dysregulated Bcl-2 family members is a hallmark of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). Therefore, targeting Bcl-2 with venetoclax has been suggested as an attractive strategy for inducing apoptosis in AML LSCs. However, the selective inhibition of Bcl-2 in AML often leads to upregulation of Mcl-1, another dominant anti-apoptotic Bcl-2 family protein conferring venetoclax resistance.

Methods: We assessed the combined effect of venetoclax and arsenic trioxide (ATO) on leukaemic cell viability, apoptosis, combination index, and cell cycle in the human LSC-like KG1 and KG1a cells. The synergistic effect of venetoclax and ATO on apoptosis was also examined in primary CD34+ and CD34+CD38- LSCs from the bone marrow (BM) of AML patients, and compared with those from healthy donors.

Results: Venetoclax efficiently impaired cell viability and dose-dependently promoted apoptosis when combined with ATO; their synergism was aptly represented by the combination index. The combination of venetoclax and ATO impaired cell cycle progression by restricting cells within the sub-G1 phase and facilitating caspase-dependent apoptotic cell death associated with the loss of mitochondrial membrane potential, while sparing healthy BM haematopoietic stem cells. Mechanistically, ATO mitigated venetoclax-induced upregulation of Mcl-1 by the inhibition of AKT and ERK, along with activation of GSK-3β. This led to the Mcl-1 destabilisation, triggering Noxa and Bim to facilitate apoptosis and the consequent activation of the apoptosis executioner protein Bak. Moreover, the combination promoted phosphorylation of ATM, Chk2, p38, and H2AX, indicating an active DNA damage response.

Conclusions: Our findings demonstrate the synergistic, preferential antileukaemic effects of venetoclax and ATO on LSCs, providing a rationale for preclinical and clinical trials by combining these agents already being used in clinical practice to treat acute leukaemia.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Jang, Ji Eun(장지은) ORCID logo https://orcid.org/0000-0001-8832-1412
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Chung, Hae Rim(정해림) ORCID logo https://orcid.org/0000-0002-7926-9285
Cho, Hyunsoo(조현수) ORCID logo https://orcid.org/0000-0003-2651-6403
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