Deciphering the role of microRNA-708 in precursor B-cell acute lymphoblastic leukemia biology.

摘要

MicroRNAs (miRs) are known to play major roles in both normal hematopoietic differentiation, as well as hematopoietic malignancies. In this work, we report that miR-708; a little studied miR, is up-regulated in most B-cell acute lymphoblastic leukemia (B-ALL) cell lines and primary patient samples compared to hematopoietic stem-progenitor cells (HSPCs) and mature healthy B-cells. Our first hypothesis in this regard was that miR-708 has an oncogene-like function in B-ALL biology. To test this hypothesis, we performed loss/gain of function assays to examine effect of miR-708 modulation on B-ALL cell proliferation. While overexpression of miR-708 failed to alter cell proliferation rate, knock-down of this miR conferred a growth disadvantage on B-ALL cell proliferation. Our second hypothesis was that accumulation of non-functional immature B cells in B-ALL is due to deregulated expression of miR-708 during B cell development. To test this hypothesis, we overexpressed miR-708 in donor murine hematopoietic progenitor (Lin-) cells and monitored their hematopoietic differentiation in recipient mice following bone marrow transplantation. Post transplantation, we failed to observe any influence of miR-708 on hematopoietic differentiation of Lin- cells. In addition, we also observed a positive correlation that exists between expression pattern of miR-708 and its host gene OdZ4. Hence, we hypothesize that up-regulated miR-708 could be a passenger of up-regulated OdZ4 in B-ALL. To test this hypothesis, we are currently examining effects of OdZ4 knock-down on B-ALL cell proliferation. In future we also propose to examine if miR-708 cooperates with OdZ4 function in B-ALL. Future work also needs to address if miR-708 affects oncogenic processes, other than growth, that could be involved in B-ALL biology.