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

V.P. Čokić (1) , Pascal Mossuz (2, 3) , Jing Han (4, 5) , Nuria Socoro (3) , B.B. Beleslin-Čokić (6) , Olivera Mitrović (1) , Tijana Subotički (1) , Miloš Diklić (1) , Danijela Leković (1) , Mirjana Gotić (1) , R.K. Puri (5) , Constance Tom Noguchi (7) , A.N. Schechter (7)

1 University Medical Center, Belgrade University, Belgrade, Serbia.
2 IBP - Institut de Biologie et de Pathologie [CHU Grenoble]
3 TIMC-IMAG-TheREx - Thérapeutique Recombinante Expérimentale
4 CIS - Chair of Complex and Intelligent Systems
5 FDA - U.S. Food and Drug Administration
6 KCS - Clinical Center of Serbia
7 NIH - National Institutes of Health [Bethesda, MD, USA]

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.

Domaines: Sciences du Vivant [q-bio]

V.P. Čokić, Pascal Mossuz, Jing Han, Nuria Socoro, B.B. Beleslin-Čokić, et al.. Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway. PLoS ONE, 2015, 10 (8), pp.e0135463. ⟨10.1371/journal.pone.0135463⟩. ⟨hal-02299029⟩