BCR/ABL Post-Translationally Enhances hnRNP E2 Expression and Translation-Inhibitory Function through the Activation of ERK1/2 Mitogen-Activated Protein Kinases.

Impaired differentiation is a common feature of many hematological malignancies including blast crisis chronic myelogenous leukemia (CML-BC). We previously reported that expression of the RNA binding protein hnRNP E2 is enhanced in CML-BC patient samples by the activity of BCR/ABL oncogenic kinase which uses hnRNP E2 to suppress translation of C/EBP alpha, the main regulator or granulocytic differentiation. Here we show that hnRNP E2 protein but not mRNA expression correlates with BCR/ABL levels in mouse 32Dcl3 myeloid progenitor cell clones expressing different levels of p210 BCR/ABL, and in the BCR/ABL-inducible TonB.210 cell line. Furthermore, exposure of 32D-BCR/ABL cells to imatinib or to the HSP90 inhibitor 17-AAG, which induces BCR/ABL proteasome-dependent degradation, results in downregulation of hnRNP E2 protein levels. Mechanistically, it appears that increased hnRNP E2 expression depends on BCR/ABL-induced post-translational modifications that increase hnRNP E2 protein stability and prevent its proteasome-dependent degradation. Indeed, we have evidence that hnRNP E2 is associated with PRMT5 arginine-methyltransferase and undergoes phosphorylation in K562 cells. Accordingly, inhibition of the mitogen activated ERK1/2 kinases by PD098059 and U0126 reduces hnRNP E2 levels and, in turn, hnRNP E2 binding to the C-rich element contained in the uORF of c/ebp alpha mRNA. Thus, activation of MAPK might be required for the hnRNP E2-dependent suppression of myeloid maturation in CML-BC.