title: Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: The Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ding
authors.forename: Nupur
authors.initials: N
authors.lastname: Dasgupta
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Du
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species; D002787:Sterol Esterase / Q000235:genetics*
chemical_list: D016213:Cyclins; D017382:Reactive Oxygen Species; D018844:Cyclin-Dependent Kinases; D002787:Sterol Esterase