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Blood, 15 January 2008, Vol. 111, No. 2, pp. 816-828.
Prepublished online as a Blood First Edition Paper on October 9, 2007; DOI 10.1182/blood-2007-05-090472.
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Submitted May 16, 2007
Accepted October 2, 2007
Identification of novel post-transcriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis
Anna M Eiring, Paolo Neviani, Ramasamy Santhanam, Joshua J Oaks, Ji Suk Chang, Mario Notari, William Willis, Carlo Gambacorti-Passerini, Stefano Volinia, Guido Marcucci, Michael A. Caligiuri, Gustavo W Leone, and Danilo Perrotti*
Human Cancer Genetics Program, Dept. Molecular Virology, Immunology & Medical Genetics & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
S. Gerardo Hospital, University of Milano Bicocca, Monza, Italy
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy
* Corresponding author; email: danilo.perrotti{at}osumc.edu.
Several RNA binding proteins (RBPs) have been implicated in the progression of chronic myelogenous leukemia (CML) from the indolent chronic phase to the aggressively fatal blast crisis. In the latter phase, expression and function of specific RBPs are aberrantly regulated at transcriptional or post-translational levels by the constitutive kinase activity of the BCR/ABL oncoprotein. As a result, altered expression/function of RBPs leads to increased resistance to apoptotic stimuli, enhanced survival, growth advantage and differentiation arrest of CD34+ progenitors from CML blast crisis patients. Here, we identified the mRNAs bound to the hnRNP A1, hnRNP E2, hnRNP K, and La/SSB RBPs in BCR/ABL-transformed myeloid cells. Interestingly, we found that the mRNA encoding the transcription factor E2F3 associates to hnRNP A1 through a conserved binding site located in the E2F3 3'UTR. E2F3 levels were upregulated in CML-BCCD34+ in a BCR/ABL-kinase- and hnRNP A1 shuttling-dependent manner. Moreover, by using shRNA-mediated E2F3 knock-down and BCR/ABL-transduced lineage-negative bone marrow cells from E2F3+/+ and E2F3-/- mice we show that E2F3 expression is important for BCR/ABL clonogenic activity and in vivo leukemogenic potential. Thus, the complexity of the mRNA:RBP network, together with the discovery of E2F3 as an hnRNP A1-regulated factor, outlines the relevant role played by RBPs in post-transcriptional regulation of CML development and progression.
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