Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia

Yunseon Jang; Jeong Suk Koh; Jung-Hyun Park; Suyoung Choi; Pham Thi Thuy Duong; Bu Yeon Heo; Sang Woo Lee; Jung Yeon Kim; Myung-Won Lee; Seok-Hwan Kim; Ik-Chan Song

doi:10.20944/preprints202311.1993.v1

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preprints.org > biology and life sciences > other > doi: 10.20944/preprints202311.1993.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia

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Version 1 : Received: 29 November 2023 / Approved: 30 November 2023 / Online: 30 November 2023 (13:38:57 CET)

A peer-reviewed article of this Preprint also exists.

Jang, Y.; Koh, J.S.; Park, J.-H.; Choi, S.; Duong, P.T.T.; Heo, B.Y.; Lee, S.W.; Kim, J.Y.; Lee, M.-W.; Kim, S.-H.; Song, I.-C. Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia. Int. J. Mol. Sci. 2024, 25, 2140. Jang, Y.; Koh, J.S.; Park, J.-H.; Choi, S.; Duong, P.T.T.; Heo, B.Y.; Lee, S.W.; Kim, J.Y.; Lee, M.-W.; Kim, S.-H.; Song, I.-C. Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia. Int. J. Mol. Sci. 2024, 25, 2140.

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating acquisition of a rapid supply of ATP for proliferation in AML. Therefore, targeting of mesothelin presents a potentially promising approach for mitigating the progression of AML through inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Keywords

mesothelin; acute myeloid leukemia; glycolysis; oxygen consumption rate

Subject

Biology and Life Sciences, Other

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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