Abstract
RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies. Here we show that RUNX3 plays an important regulatory role in normal human erythropoiesis. The impact of altering RUNX3 expression on erythropoiesis was determined by transducing human CD34+ cells with RUNX3 overexpression or shRNA knockdown vectors. Analysis of RUNX3 mRNA expression showed that RUNX3 levels decreased during erythropoiesis. Functionally, RUNX3 overexpression had a modest impact on early erythroid growth and development. However, in late-stage erythroid development, RUNX3 promoted growth and inhibited terminal differentiation with RUNX3 overexpressing cells exhibiting lower expression of glycophorin A, greater cell size and less differentiated morphology. These results suggest that suppression of RUNX3 is required for normal erythropoiesis. Overexpression of RUNX3 increased colony formation in liquid culture whilst, corresponding RUNX3 knockdown suppressed colony formation but otherwise had little impact. This study demonstrates that the downregulation of RUNX3 observed in normal human erythropoiesis is important in promoting the terminal stages of erythroid development and may further our understanding of the role of this transcription factor in haematological malignancies.
Highlights
RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies
RUNX proteins are a family of transcription factors (RUNX1, 2 and 3) that participate in important developmental processes: RUNX1 is essential for definitive h aematopoiesis[2,3]; RUNX2 is involved in skeletal d evelopment[4,5]; and RUNX3 is essential for n eurogenesis[6,7], T cell d evelopment[8,9] and gastric epithelium growth[10]
To determine whether suppression of RUNX3 is functionally important to normal erythroid development, human cord blood derived CD34+ haematopoietic stem and progenitor cells (HSPC) were stably transduced with a vector co-expressing RUNX3 and DsRed (Supplemental Fig. S1)
Summary
RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies. In late-stage erythroid development, RUNX3 promoted growth and inhibited terminal differentiation with RUNX3 overexpressing cells exhibiting lower expression of glycophorin A, greater cell size and less differentiated morphology These results suggest that suppression of RUNX3 is required for normal erythropoiesis. This study demonstrates that the downregulation of RUNX3 observed in normal human erythropoiesis is important in promoting the terminal stages of erythroid development and may further our understanding of the role of this transcription factor in haematological malignancies. Transcription factors play an important role in the establishment of haematopoietic lineages by regulating the survival and proliferation of haematopoietic stem and progenitor cells (HSPC), and cell fate decisions and differentiation[1] Their disruption can lead to changes in haematopoietic differentiation and the subsequent development of haematopoietic malignancies. Considering the growing evidence for an important role in haematopoiesis and haematological malignancies, this study sought to establish the role of RUNX3 expression on normal human erythroid development
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