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

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

Up-regulation of cyclin proteins in <i>lal−/−</i> bone marrow MDSCs.

<p>Up-regulation of cyclin proteins in <i>lal−/−</i> bone marrow MDSCs.</p

Decreases of large G-protein superfamily in <i>lal−/−</i> bone marrow MDSCs.

<p>Decreases of large G-protein superfamily in <i>lal−/−</i> bone marrow MDSCs.</p

Up-regulation of histone cluster genes in <i>lal−/−</i> bone marrow MDSCs.

<p>Up-regulation of histone cluster genes in <i>lal−/−</i> bone marrow MDSCs.</p

Increases of large G-protein superfamily in <i>lal−/−</i> bone marrow MDSCs.

<p>Increases of large G-protein superfamily in <i>lal−/−</i> bone marrow MDSCs.</p

Cell cycle analysis of lal−/− bone marrow MDSCs.

<p><b>A</b>). Cell cycle analysis of CD11b⁺ly6G⁺ MDSCs from the bone marrow of <i>lal+/+</i> mice and <i>lal−/−</i> mice; <b>B</b>). The G1/G0 phase, S phase and G2/M phase of CD11b⁺Ly6G⁺ MDSCs from the bone marrow of <i>lal+/+</i> mice and <i>lal−/−</i> mice were statistically analyzed. Results are means of 4 independent FACS experiments. n = 4, **, p<0.01, *, p<0.5.</p

Up and down-regulation of mitochondrial NADH dehydrogenases in <i>lal−/−</i> bone marrow MDSCs.

<p>Up and down-regulation of mitochondrial NADH dehydrogenases in <i>lal−/−</i> bone marrow MDSCs.</p

Up-regulation of metabolic enzyme genes in glycolysis, citric acid cycle and glycogen syntheses in <i>lal−/−</i> bone marrow MDSCs.

<p>Up-regulation of metabolic enzyme genes in glycolysis, citric acid cycle and glycogen syntheses in <i>lal−/−</i> bone marrow MDSCs.</p