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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3744-3753.
Prepublished online as a Blood First Edition Paper on December 18, 2008; DOI 10.1182/blood-2008-09-178707.
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Submitted September 11, 2008
Accepted November 22, 2008
Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase, Itch for degradation
Deepa Sampath*, George A Calin, Vinay K. Puduvalli, Gopal Gopisetty, Cristian Taccioli, Chang-Gong Liu, Brett Ewald, Chaomei Liu, Michael J Keating, and William Plunkett
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: dsampath{at}mdanderson.org.
Chronic lymphocytic leukemia (CLL) is characterized by cells that exhibit dysfunctional apoptosis. Here, we show, deacetylase inhibition led to the E2F1- and myc-mediated transcriptional activation of the microRNA, miR106b in primary CLL cells. Induction of miR106b was associated with a downregulation in the levels of the E3-ubiquitin ligase, Itch. Decreases in Itch protein levels were associated with a reciprocal accumulation of its proapoptotic substrate, TAp73 (p73), and induction of PUMA mRNA and protein. This event was accompanied by mitochondrial dysfunction, processing of caspase-9 and apoptosis of CLL cells. Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. Thus, our results identify a novel regulatory mechanism wherein miRNA regulate cell survival by mediating the post-transcriptional downregulation of an ubiquitin ligase, leading to the induction of a proapoptotic regulator in malignant cells. Silencing of miRNA expression in CLL may selectively suppress proapoptotic pathways providing such tumors with a survival advantage. Consequently, chemotherapeutic drugs that activate miR106b could initiate a p53-independent mechanism that targets CLL cells.
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