title: High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation.
abstract: The inability of myeloid chronic myelogenous leukemia blast crisis (CML-BC) progenitors to undergo neutrophil differentiation depends on suppression of C/EBPalpha expression through the translation inhibitory activity of the RNA-binding protein hnRNP-E2. Here we show that "oncogene dosage" is a determinant factor for suppression of differentiation in CML-BC. In fact, high levels of p210-BCR/ABL are required for enhanced hnRNP-E2 expression, which depends on phosphorylation of hnRNP-E2 serines 173, 189, and 272 and threonine 213 by the BCR/ABL-activated MAPK(ERK1/2). Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Similarly, pharmacologic inhibition of MAPK(ERK1/2) activity decreases hnRNP-E2 binding to the 5'UTR of C/EBPalpha mRNA by impairing hnRNP-E2 phosphorylation and stability. This, in turn, restores in vitro and/or in vivo C/EBPalpha expression and G-CSF-driven neutrophilic maturation of differentiation-arrested BCR/ABL(+) cell lines, primary CML-BC(CD34+) patient cells and lineage-negative mouse bone marrow cells expressing high levels of p210-BCR/ABL. Thus, increased BCR/ABL oncogenic tyrosine kinase activity is essential for suppression of myeloid differentiation of CML-BC progenitors as it is required for sustained activation of the MAPK(ERK1/2)-hnRNP-E2-C/EBPalpha differentiation-inhibitory pathway. Furthermore, these findings suggest the inclusion of clinically relevant MAPK inhibitors in the therapy of CML-BC.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 23240, USA.
authors.forename: Ji Suk
authors.initials: JS
authors.lastname: Chang
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Edward
authors.initials: E
authors.lastname: Briercheck
authors.forename: Mattia
authors.initials: M
authors.lastname: Ronchetti
authors.forename: Denis C
authors.initials: DC
authors.lastname: Roy
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D004791:Enzyme Inhibitors; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D016044:Fusion Proteins, bcr-abl; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3