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

High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation / Chang, Js; Santhanam, R; Trotta, R; Neviani, P; Eiring, Am; Briercheck, E; Ronchetti, M; Roy, Dc; Calabretta, Bruno; Caligiuri, Ma; Perrotti, D.. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 110:3(2007), pp. 994-1003. [10.1182/blood-2007-03-078303]

High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation

CALABRETTA, Bruno;
2007

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
2007
110
3
994
1003
High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation / Chang, Js; Santhanam, R; Trotta, R; Neviani, P; Eiring, Am; Briercheck, E; Ronchetti, M; Roy, Dc; Calabretta, Bruno; Caligiuri, Ma; Perrotti, D.. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 110:3(2007), pp. 994-1003. [10.1182/blood-2007-03-078303]
Chang, Js; Santhanam, R; Trotta, R; Neviani, P; Eiring, Am; Briercheck, E; Ronchetti, M; Roy, Dc; Calabretta, Bruno; Caligiuri, Ma; Perrotti, D.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/595110
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