8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia

Jiamin Guo; Ralf Buettner; Li Du; Zhenlong Li; Wei Liu; Rui Su; Zhenhua Chen; Yuan Che; Yi Zhang; Rui Ma; Le Xuan Truong Nguyen; Roger E Moore; Pathak Khyatiben; Min-Hsuan Chen; Pirrotte Patrick; Xiwei Wu; Guido Marcucci; Lili Wang; David Horne; Jianjun Chen; Yanzhong Yang; Steven T Rosen

doi:10.1038/s41375-024-02222-w

8-Cl-Ado and 8-NH₂-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia

Leukemia. 2024 Apr 20. doi: 10.1038/s41375-024-02222-w. Online ahead of print.

Authors

Jiamin Guo^{1

2}, Ralf Buettner³, Li Du³, Zhenlong Li³, Wei Liu³, Rui Su⁴, Zhenhua Chen⁴, Yuan Che⁴, Yi Zhang⁵, Rui Ma³, Le Xuan Truong Nguyen⁶, Roger E Moore⁷, Pathak Khyatiben^{7

8}, Min-Hsuan Chen⁹, Pirrotte Patrick^{7

8}, Xiwei Wu⁹, Guido Marcucci⁶, Lili Wang⁴, David Horne¹⁰, Jianjun Chen⁴, Yanzhong Yang⁵, Steven T Rosen¹¹

Affiliations

¹ Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA. jguo@coh.org.
² Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. jguo@coh.org.
³ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.
⁴ Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
⁵ Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA.
⁶ Department of Hematologic Malignancies Translational Science and Division of Leukemia, City of Hope, Duarte, CA, USA.
⁷ Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA.
⁸ Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
⁹ Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA.
¹⁰ Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
¹¹ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. srosen@coh.org.

PMID: 38643304
DOI: 10.1038/s41375-024-02222-w

Abstract

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.