Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway

• Published in: PloS one Vol. 10; no. 8; p. e0135463
• Main Authors: Čokić, Vladan P., Mossuz, Pascal, Han, Jing, Socoro, Nuria, Beleslin-Čokić, Bojana B., Mitrović, Olivera, Subotički, Tijana, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Puri, Raj K., Noguchi, Constance Tom, Schechter, Alan N.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.08.2015; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Apoptosis; Blood cancer; Bone marrow; Cancer; CD34 antigen; Cell growth; Diabetes; DNA microarrays; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Granulocytes; Hematologic Neoplasms - genetics; Hematologic Neoplasms - metabolism; Hematology; Humans; Janus kinase 2; Kidney diseases; Kinases; Laboratories; Leukemia; Leukocytes (granulocytic); Life Sciences; Male; MAP kinase; Medical research; Molecular chains; Mutation; Myelofibrosis; Myeloid Cells - metabolism; Myeloid Cells - pathology; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - pathology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasms; Oligonucleotide Array Sequence Analysis; Pathogenesis; Pattern recognition; Peripheral blood; Phosphorylation; Polycythemia; Polycythemia vera; Proteins; Proteomics; Rac2 protein; Regulators; Runx1 protein; Signal Transduction; Signaling; Studies; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors; Serbia; France; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135463

The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34+ cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34+ cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34+ cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34+ cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34+ cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34+ cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling.