Pathogenetic Alterations in Gene Specific RNA Translat*

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): Over the last two decades, extensive studies performed in our lab as well as the investigations of many others have established that alterations in major cytokine signal transduction pathways play a dominant role in the molecular pathogenesis of the myeloproliferative disorders. Most of the emphasis of these studies has focused on the effects that dysregulated Ras, MARK, PI3K, Akt and other signaling components have on transcriptional events. Indeed, not only have the majority of pathogenetic investigations focused on the effect of transcription but even the development of targeted therapeutics has revolved around this area of mechanistic control. However, recent publications in other cell systems have examined the immediate effect of Ras or Akt signaling blockade on transcription with only modest effects observed (e.g., only 16 genes exhibiting 3-fold or greater changes in total mRNA levels). By contrast, 705 genes were identified as exhibiting significant fold changes (>3-fold) at the translational level (polysome-associated RNA), and many were altered by greater than 10-fold. These investigations strongly suggest that signal transduction pathways influence the expression of target genes predominantly at the translational (RNA to protein) level, and that the primary oncogenic effect of Ras and Akt signaling may be to alter the translational efficiency of existing mRNAs. We seek to examine this possibility in four of the myeloproliferative disorders - chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and juvenile myelomonocytic leukemia. Each of these four disorders is known to involve dysregulation of Ras signaling albeit to varying degrees and by varying underlying mechanisms. Taking advantage of the availability of primary patient samples via the Principal Investigator, we will: (1) perform microarray analyses on polysome-associated (actively translated) versus total mRNA, (2) assess the functional status of general translation initiation regulatory factors, (3) profile the sequence-specific RNA-binding proteins which interact with 5'- and 3'- untranslated regulatory RNA sequences of eight selected phenotype-determining target genes, and (4) examine in detail how the translational regulation of two selected target genes of interest is altered as a consequence of altered Ras pathway signaling in MPD cells. We believe this line of investigation will elucidate whether translational efficiency of existing mRNAs plays a pivotal role in MPDs pathogenesis.