Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis.
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.
Eiring
Anna M
AM
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, USA.
Neviani
Paolo
P
Santhanam
Ramasamy
R
Oaks
Joshua J
JJ
Chang
Ji Suk
JS
Notari
Mario
M
Willis
William
W
Gambacorti-Passerini
Carlo
C
Volinia
Stefano
S
Marcucci
Guido
G
Caligiuri
Michael A
MA
Leone
Gustavo W
GW
Perrotti
Danilo
D
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050699:E2F3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D018952:Antigens, CD34; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C490840:E2f3 protein, mouse; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl