Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase, Itch for degradation

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Blood First Edition Paper, prepublished online December 18, 2008; DOI

10.1182/blood-2008-09-178707.

Specific activation of microRNA106b enables the p73 apoptotic response in

chronic lymphocytic leukemia by targeting the ubiquitin ligase, Itch for

degradation

Deepa Sampath*, A Calin, Vinay K. Puduvalli, Gopal Gopisetty, Cristian

Taccioli, Chang-Gong Liu, Brett Ewald, Chaomei Liu, J Keating, and

Plunkett

Department of Experimental Therapeutics, University of Texas M.D.

Cancer Center, Houston, TX, United States

Department of Neuro-Oncology, University of Texas M.D. Cancer Center,

Houston, TX, United States

Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States

Department of Leukemia, University of Texas M.D. Cancer Center,

Houston, TX, United States

* Corresponding author; email: dsampath@... .

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.