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Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators

Leukemia volume 20, pages 1885–1888 (2006)Cite this article

Myeloproliferative disorders (MPDs) are clonal proliferative diseases of the hematopoietic stem cells. After an initial phase, they may progress to an acute syndrome. V617F mutation of the Janus kinase 2 (JAK2) kinase are found in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. BCR-ABL fusion occurs in chronic myeloid leukemia, and a variety of fusions involving platelet-derived growth factor and fibroblast growth factor (FGF) receptors are found in other MPDs.1 Fusion kinases that result from a translocation are made of a constitutively activated kinase domain and an N-terminal region encoded by a partner gene. The activated kinase triggers sustained proliferation and survival of the hematopoietic cells, but maturation is not affected.

We studied the gene expression profiles of murine Ba/F3 cells transfected by various oncogenic MPD kinases by using whole-genome Affymetrix 430 2.0 mouse oligonucleotide microarrays (www.Affymetrix.com). Ba/F3 cells were grown in Rosewell Park Memorial Institute (RPMI) medium supplemented with 10% fetal calf serum (FCS) and interleukin-3 (IL-3). Expression of an MPD kinase bypasses the IL-3 dependence of Ba/F3 cells. RNA was extracted by using Trizol (Trizol Reagent, Invitrogen Life Technologies, Carlsbad, CA, USA) from frozen pellets of: (i) Ba/F3 cells; (ii) Ba/F3 transfected with different pCDNA expression vectors expressing a mutant, kinase-defective FOP-FGFR1 KD or an oncogenic MPD kinase (BCR-ABL, FOP-FGFR1, CEP1-FGFR1, BCR-FGFR1); and (iii) Ba/F3 transfected by the MIGR vector, either empty (MIGR) or with JAK2 (JAK2 WT, mutated V617F JAK2 or mutated V617F IND JAK2, that is, able to grow independently of IL-3).2 Before RNA extraction, cells were starved for 7 h in RPMI plus 0.5% FCS. RNA integrity was controlled by microanalysis (Agilent Bioanalyzer, Palo Alto, CA, USA). Preparation of cRNA, hybridizations, washes, detection and quantification were performed as recommended by the supplier (www.Affymetrix.com). Data were analyzed by the robust multichip average (RMA) method in R using Bioconductor and associated package. Before analysis, a filtering process removed from the data set the genes with low and poorly measured expression as defined by an expression value inferior to 100 U in all samples, retaining 17.885 genes/expressed sequence tags (ESTs). For paired samples, RNA was prepared independently from different cultures of cells. The correlation between paired samples ranged between 0.97 and 0.98.

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Acknowledgements

We thank B Delaval and MJ Mozziconacci for discussions and advices, and P Dubreuil (Marseille) and NC Cross (Salisbury, UK) for reagents. This work was supported by the Institut Paoli-Calmettes, Inserm, and grants from the Institut National du Cancer/Cancéropôle (ACI2005) and the Association Laurette Fugain (2005).

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  1. H Lelièvre and N Cervera: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France

    H Lelièvre, N Cervera, P Finetti, F Bertucci & D Birnbaum

  2. U362 Inserm, Institut Gustave Roussy, Villejuif, France

    F Delhommeau & W Vainchenker

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  1. H Lelièvre
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Correspondence to D Birnbaum.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Lelièvre, H., Cervera, N., Finetti, P. et al. Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators. Leukemia 20, 1885–1888 (2006). https://doi.org/10.1038/sj.leu.2404361

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