MiRNA in ALL
Bone marrow microenvironment influence on leukemic miRNA expression
Acute lymphoblastic leukemia (ALL) cells have many features in common with normal B cell progenitors, including their ability to respond to diverse signals in the bone marrow microenvironment. As such, it is not surprising that the bone marrow is the site of initiation, progression, and often relapse of aggressive hematopoietic malignancies. Bone marrow derived signals influence many elements of both steady state hematopoietic cell development and tumor cell biology through modulation of gene expression. MiRNAs define one regulatory class of small non-coding RNAs that have been shown to be increasingly important in hematopoietic cell biology. Alteration of miRNA expression has been shown to impact on tumor cell survival and therapeutic response with the association of specific miRNAs and progression of disease also reported. These observations provide the rationale for considering regulation of tumor cell miRNA expression profiles, or miRNA function, by bone marrow microenvironment signals as one mechanism by which the marrow niche influences leukemic cell characteristics. Preliminary observations have identified miR-221 and miR-222 as being down-regulated in leukemic cells following co-culture with primary human bone marrow niche cells (stromal cells and osteoblasts). MiR-221/222 regulate cell cycle progression, in part, through validated downstream targets including the cell cycle inhibitor p27. Reduced miR-221/222 following co-culture with microenvironment cues from adherent cells or through transduction of a miRNA sponge results in accumulation of tumor cells in a quiescent (G0) phase coincident with chemoresistance. Based on these observations we will continue investigation of bone marrow microenvironment regulation of miR-221/222 as one mechanism by which leukemic cell quiescence is maintained, contributing to evasion of chemotherapy agents and potential to contribute to relapse of disease.