MICRORNA-BASED TARGETING OF HEDGEHOG PATHWAY IN CML STEM/PROGENITOR CELLS

Mounting evidence supports central functions of leukemic stem cells (LSCs) in leukemogenesis, due to its distinct high potentials of self-renewal, pluripotent differentiation and apoptosis-resistance, contributing to therapeutic resistance and cancer progression. Self-renewal is discriminated from other proliferating processes since at least one of progeny is identical to the primary stem cell. Dysregulation of stem cell self-renewal is a likely requisite for the initiation, progression, and therapeutic resistance of cancer. A number of studies have showed that quiescent LSCs are relatively resistant to therapies that target rapidly dividing leukemia cells, and thus contribute to avoid apoptosis, renew themselves, and survive long term. Therefore, inhibiting/eliminating LSCs will provide a new effective therapeutic approach for the treatment of leukemias. However, the mechanistic roles of LSCs in leukemogenesis are not well understood. The discovery of microRNAs (miRNAs), a large family of small non-coding RNA molecules, has provided a newer perspective on cancer research. Emerging evidence suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, metastasis, and drug resistance. Apart from the oncogenic and tumor suppressive roles of miRNAs as key regulators of gene expression in tumorigenesis, these small RNAs have been also recognized as potential modulators of LSC characteristics mediated through the regulation of multiple pro-oncogenic signaling pathways. Our recent studies showed that abnormal expression of certain miRNAs are involved in dysregulation of essential chronic myeloid leukemia (CML) stem cell maintenance pathways such as Hedgehog pathway, resulting in unlimited self-renewal and cancer progression. In this regard, our observations suggest a model in which miRNA functions may be required to efficiently impair the oncogenic potential of stem cell maintenance pathways. Taken together, it seems that targeting CML stem cell signature genes along with relevant miRNAs will provide a novel and more effective therapeutic approach for the eradication of CML stem cells, which will lead to the inhibition of CML recurrence.