Gene Profile of Myeloid-derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-out Mice

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Mar 3

PMID 22383970

Citations 19

Authors

Cong Yan

Xinchun Ding

Nupur Dasgupta

Lingyan Wu

Hong Du

Affiliations

Soon will be listed here.

Abstract

Background: Lysosomal acid lipase (LAL) controls development and homeostasis of myeloid lineage cells. Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm.

Methodology/principal Findings: Affymetrix GeneChip microarray analysis identified detailed intrinsic defects in Ly6G(+) myeloid lineage cells of LAL knock-out (lal-/-) mice. Ingenuity Pathway Analysis revealed activation of the mammalian target of rapamycin (mTOR) signaling, which functions as a nutrient/energy/redox sensor, and controls cell growth, cell cycle entry, cell survival, and cell motility. Loss of the LAL function led to major alteration of large GTPase and small GTPase signal transduction pathways. lal-/- Ly6G(+) myeloid cells in the bone marrow showed substantial increase of cell proliferation in association with up-regulation of cyclin and cyclin-dependent kinase (cdk) genes. The epigenetic microenvironment was significantly changed due to the increased expression of multiple histone cluster genes, centromere protein genes and chromosome modification genes. Gene expression of bioenergetic pathways, including glycolysis, aerobic glycolysis, mitochondrial oxidative phosphorylation, and respiratory chain proteins, was also increased, while the mitochondrial function was impaired in lal-/- Ly6G(+) myeloid cells. The concentration of reactive oxygen species (ROS) was significantly increased accompanied by up-regulation of nitric oxide/ROS production genes in these cells.

Conclusions/significance: This comprehensive gene profile study for the first time identifies and defines important gene pathways involved in the myeloid lineage cells towards MDSCs using lal-/- mouse model.

Citing Articles

Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.

Buerger M, Amor M, Akhmetshina A, Bianco V, Perfler B, Zebisch A Int J Mol Sci. 2024; 25(20).

PMID: 39456786 PMC: 11506919. DOI: 10.3390/ijms252011001.

LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung cancer.

Zhao T, Liu S, Hanna N, Jalal S, Ding X, Wan J J Immunother Cancer. 2023; 11(3).

PMID: 36914206 PMC: 10016256. DOI: 10.1136/jitc-2022-006272.

Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells.

Zhao T, Liu S, Ding X, Johnson E, Hanna N, Singh K JCI Insight. 2022; 7(17).

PMID: 35917184 PMC: 9536279. DOI: 10.1172/jci.insight.156623.

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells.

Alissafi T, Hatzioannou A, Mintzas K, Barouni R, Banos A, Sormendi S J Clin Invest. 2018; 128(9):3840-3852.

PMID: 29920188 PMC: 6118632. DOI: 10.1172/JCI120888.

Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice.

Zhao T, Ding X, Yan C, Du H J Biol Chem. 2017; 292(47):19198-19208.

PMID: 28924047 PMC: 5702662. DOI: 10.1074/jbc.M116.773093.

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