Understanding the biology of Chronic Myelogenous Leukemia (CML) disease progression is of critical importance, as the advanced stage of the disease is often associated with a dismal outcome. We extensively reported that altered mRNA metabolism is a key feature of blast crisis CML (CML-BC). Indeed, loss-of-function of tumor suppressors (e.g. PP2A, C/EBPa) and enhanced expression of pro-oncogenic factors (e.g. MYC, MDM2 and BCL-XL) in CML-BC results from aberrant mRNA processing, nuclear export and/or translation. Given that a) BCR/ABL levels are increased in the CML-BC leukemia-initiating cell; b) a causal relationship exists between BCR/ABL levels/activity and altered mRNA metabolism; and c) molecular and/or pharmacologic interference with the expression and/or activity of the RNA binding proteins hnRNP A1, E2 and K antagonizes both in vitro and in vivo BCR/ABL leukemogenesis by impairing proliferation, inhibiting survival and/or restoring differentiation of BCR/ABL+ hematopoietic progenitors; the hypothesis driving this proposal is that BCR/ABL initiates a hierarchical activation of signals leading to a temporally- and developmentally-organized increase in the expression/function of these RNA binding proteins, and that this represents an essential step for disease progression. Based on these considerations, the overall objective is to further understand the importance of altered mRNA metabolism for the pathophysiology of CML-BC through an integrated in vitro and in vivo analysis of the temporal changes in expression/function of the BCR/ABL-regulated hnRNPs and of their interplay/interaction with other post-transcriptional regulators of gene expression (e.g. microRNAs). Specifically, CML-BC specimens, the unique SCL-tTA-BCR/ABL mouse model of disease progression and BCR/ABL+ cell lines will be used to assess whether 1) BCR/ABL-dependent regulation of hnRNP A1, K and E2 expression/activity follows a hierarchical order and at which stage of the CML stem/progenitor cell development it occurs; 2) in vivo modulation of hnRNP A1, E2 and K expression/activity prevents CML blastic transformation; and 3) in vitro and in vivo the role of miR-223 and miR-328 in the regulation of hnRNP E2 translation-modulatory activity in CML-BC. If successful, this investigation will formally establish a functional link between CML progression, BCR/ABL expression and altered mRNA metabolism, and will indicate the incorporation of drugs capable of antagonizing the BCR/ABL-hnRNP-regulated pathways in the therapy of Ph1 leukemias and, perhaps, of other cancers characterized by similar alteration in mRNA metabolism. Note that our discovery of the BCR/ABL-hnRNP A1-SET-PP2A inhibitory pathway and of its importance as a feasible therapeutic target in imatinib/dasatinib-sensitive and -resistant CML-BC and Ph1 ALL is in the process to be translated into clinical trials. Hence, the strong relevance of the proposed studies for basic and translational cancer research.
Understanding the mechanisms underlying CML disease progression is of critical importance, as CML-BC often does not respond to conventional kinase inhibitor therapy and is usually associated with a dismal outcome. If the proposed studies will determine modulation of RNA binding protein expression and function antagonize disease progression and efficiently induce apoptosis in the leukemia-initiating cells, the anti- leukemic effects of drug capable of altering the effects of aberrant hnRNP activity may be assessed in clinical trials. Thus, it is clear that, if successful, the proposed research will have a strong impact on leukemia research and patient care. ? ? ?
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