High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation.
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.
Chang
Ji Suk
JS
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 23240, USA.
Santhanam
Ramasamy
R
Trotta
Rossana
R
Neviani
Paolo
P
Eiring
Anna M
AM
Briercheck
Edward
E
Ronchetti
Mattia
M
Roy
Denis C
DC
Calabretta
Bruno
B
Caligiuri
Michael A
MA
Perrotti
Danilo
D
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
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