Faculty Collaboration Database

Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis. Blood 2008 Jan 15;111(2):816-28

Date

10/11/2007

Pubmed ID

17925491

Pubmed Central ID

PMC2200861

DOI

10.1182/blood-2007-05-090472

Scopus ID

2-s2.0-38349102790 (requires institutional sign-in at Scopus site)   40 Citations

Abstract

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 posttranslational 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 patients in CML blast crisis. Here, we identify the mRNAs bound to the hnRNP-A1, hnRNP-E2, hnRNP-K, and La/SSB RBPs in BCR/ABLtransformed 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' untranslated region (UTR). E2F3 levels were up-regulated 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 posttranscriptional regulation of CML development and progression.

Author List

Eiring AM, Neviani P, Santhanam R, Oaks JJ, Chang JS, Notari M, Willis W, Gambacorti-Passerini C, Volinia S, Marcucci G, Caligiuri MA, Leone GW, Perrotti D

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3' Untranslated Regions
Animals
Antigens, CD34
Apoptosis
Blast Crisis
Cell Survival
Cell Transformation, Neoplastic
E2F3 Transcription Factor
Female
Fusion Proteins, bcr-abl
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cells
Heterogeneous-Nuclear Ribonucleoproteins
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Male
Mice
Mice, Knockout
Protein-Tyrosine Kinases
RNA, Neoplasm
RNA-Binding Proteins