Regulator of myeloid differentiation and function:The secret life of Ikaros

Ikaros (also known as Lyf-1) was initially described as a lymphoid-specific transcription factor.Although Ikaros has been shown to regulate hematopoietic stem cell renewal,as well as the development and function of cells from multiple hematopoietic lineages,including the myeloid lineage,Ikaros has primarily been studied in context of lymphoid development and malignancy.This review focuses on the role of Ikaros in myeloid cells.We address the importance of post-transcriptional regulation of Ikaros function;the emerging role of Ikaros in myeloid malignancy;Ikaros as a regulator of myeloid differentiation and function;and the selective expression of Ikaros isoform-x in cells with myeloid potential.We highlight the challenges of dissecting Ikaros function in lineage commitment decisions among lymphoidmyeloid progenitors that have emerged as a major myeloid differentiation pathway in recent studies,which leads to reconstruction of the traditional map of murine and human hematopoiesis.

Aminoflavone upregulates putative tumor suppressor miR-125b-2-3p to inhibit luminal A breast cancer stem cell-like properties

Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated self-renewal.We previously determined that the aryl hydrocarbon receptor(AhR)agonist aminoflavone(AF)inhibits the expression of the CSC biomarkerα6-integrin(ITGA6)to disrupt the formation of luminal(hormone receptor-positive)mammospheres(3D breast cancer spheroids).In this study,we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity.AF significantly induced the expression of>70 microRNAs(miRNAs)including miR125b-2–3p,a predicted stemness gene regulator.AF-mediated miR125b-2–3p induction was validated in MCF-7 mammospheres and cells.miR125b-2–3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues.While miR125b-2–3p levels were low in MCF-7 cells,they were much lower in AHR100 cells(MCF-7 cells made unresponsive to AhR agonists).The miR125b-2–3p mimic decreased,while the antagomiR125b-2–3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells.In MCF-7 mammospheres,the miR125b-2–3p mimic decreased only ITGA6 expression although the antagomiR125b-2–3p increased ITGA6,SOX2 and MYC expression.AntagomiR125b-2–3p reversed AF-mediated suppression of ITGA6.The miR125b-2–3p mimic decreased proliferation,migration,and mammosphere formation while the antagomiR125b-2–3p increased proliferation and mammosphere formation in MCF-7 cells.The miR125b-2–3p mimic also inhibited proliferation,mammosphere formation,and migration in AHR100 cells.AF induced AhR-and miR125b2-3p-dependent anti-proliferation,anti-migration,and mammosphere disruption in MCF-7 cells.Our findings suggest that miR125b-2–3p is a tumor suppressor and AF upregulates miR125b-2–3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.