MiR-221-regulated KIT level by wild type or leukemia mutant RUNX1: a determinant of single myeloblast fate decisions that – collectively – drives or hinders granulopoiesis

Abstract

RUNX1, a master transcription factor of hematopoiesis, was shown to orchestrate both cell proliferation and differentiation during granulopoiesis by regulating microRNAs (miRs). In this study, taking advantage of the miR-ON reporter system, we monitored first, how the granulocyte colony stimulation factor (GCSF) temporally modulates the concomitant level variation of miR-221 and one of its prototypic targets, the stem cell factor receptor KIT, in single 32D^miR-ON-221 myeloblasts expressing wild type RUNX1. Second, with the same reporter system we assessed how these temporal dynamics are affected by the t(8;21)(q22;q22) acute myelogenous leukemia mutant RUNX1-MTG8 (RM8) in single 32D-RM8^miR-ON-221 myeloblasts. Depending on either wild type, or mutant, RUNX1 transcriptional regulation, the cell-context specific miR-221-regulated KIT level translates into differential single cell fate decisions. Collectively, single cell fate choices translate into either initial expansion of undifferentiated myeloblasts followed by terminal granulocyte differentiation, as it happens in normal granulopoiesis, or aggressive growth of undifferentiated myeloblasts, as it happens in RUNX1-MTG8-positive acute myelogenous leukemia. Increasing knowledge of biological changes, due to altered miRNA dynamics, is expected to have relevant translational implications for leukemia detection and treatment.