Altered mRNA metabolism in chronic myelogenous leukemia: Loss of microRNA-328 decoy activity is important for blastic transformation of leukemic progenitors.

摘要

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the pluripotent hematopoietic stem cell characterized by presence of a short minute chromosome, the Philadelphia (Ph1) chromosome, which derives from the t(9:22) reciprocal translocation. CML is clinically characterized by three distinct phases. The majority of patients present in chronic phase (CML-CP), a prolonged myeloproliferative disorder in which myeloid progenitors demonstrate enhanced survival but no change in the capacity for terminal myeloid differentiation. This initial phase, while variable in duration, can progress into an accelerated phase (CML-AP) and eventually to a rapidly fatal blast crisis (CML-BC), characterized by enhanced survival and proliferation, an increased propensity for acquisition of secondary genetic abnormalities, and the inability of progenitor cells to undergo terminal differentiation in response to stimuli (e.g. cytokines).;CML is characterized by presence of the BCR/ABL oncogenic fusion tyrosine kinase. There is evidence suggesting that enhanced BCR/ABL expression and activity contributes to CML blastic transformation; however, additional molecular mechanisms behind this transition are largely unknown. While the advent of ABL tyrosine kinase inhibitors (TKIs; e.g. Gleevec, also called Imatinib) has greatly improved the outcome and survival of CML-CP patients, the development of TKI resistance in CML-CP, and the poor long-term therapeutic response observed in most CML-BC patients, suggests that new investigation into alternative CML therapies is needed.;Altered messenger RNA (mRNA) metabolism is a feature of several different types of cancers, including CML-BC. Our laboratory has identified several sequence-specific RNA binding proteins (RBPs), including heterogeneous ribonucleoproteins (hnRNPs), whose expression and function are altered in CML-BC at transcriptional or post-translational levels. As a result, altered expression and function of RBPs leads to loss-of-function of tumor suppressors and increased expression/activity of oncoproteins involved in the enhanced survival, growth advantage, and differentiation arrest seen in CML-BCCD34+ bone marrow progenitors.;Similar to RBPs, microRNAs (miRNAs) are also post-transcriptional gene regulators that bind to mRNA in a sequence-specific manner. In particular, miRNAs act by interfering with translation of mRNA to its final protein product. In cell lines, primary mouse BCR/ABL+/lineage-bone marrow cells, and patient-derived CML-BCCD34+ myeloid progenitors, miR-328 is markedly downregulated in a BCR/ABL-MAPK-hnRNP E2-dependent manner. Restoration of miR-328 expression rescues C/EBPalpha expression and promotes differentiation in both CML-BCCD34+ progenitors and in animal models of CML-BC. Mechanistically, the C-rich miR-328 interacts with hnRNP E2 and prevents its binding to CEBPA intercistronic mRNA, thus allowing C/EBPalpha expression and directly promoting miR-328 transcription and neutrophilic differentiation. Altogether, these data unveil the ability of microRNAs to directly regulate RNA binding protein function and suggest a paradigm shift for how we currently view miRNA function.