Abstract
RUNX1 is a Runt family transcription factor that plays a critical role in normal hematopoiesis, including the differentiation and proliferation of hematopoietic cells. RUNX1 mutations, including chromosomal translocations, cause abnormal cell differentiation, but the mutation alone is not sufficient to cause leukemia. In MLL-fusion-induced leukemia, dysregulated wild-type RUNX1 can promote leukemia survival. Nevertheless, the underlying mechanisms of dysregulated wild-type RUNX1 in leukemia development have not been fully elucidated. This study overexpressed and knocked down RUNX1 expression in THP-1 human leukemia cells and CD34+ hematopoietic stem/progenitor cells to investigate the biological functions affected by dysregulated RUNX1. Our data indicated RUNX1 facilitated proliferation to promote leukemia cell growth. Furthermore, we demonstrated that RUNX1 knockdown in leukemia cells drastically diminished colony-forming ability. Finally, the RUNX1-knocked down cell depletion phenotype could be rescued by overexpression of CENPE, a cell proliferation gene and a RUNX1 direct target gene. Our results indicate a possible mechanism involving the RUNX1-CENPE axis on promoting leukemic cell growth.
Highlights
Transcription factor RUNX1, known as AML1 or CBFA-2, plays a pivotal role in normal hematopoiesis
Our results suggested that RUNX1 could induce leukemia cell growth by promoting cell proliferation, which was regulated in part by the RUNX1-CENPE axis
The apoptotic ratio in the RUNX1 knocked down (KD) group was significantly increased compared to that in the control group. These results suggested that reduced proliferation capacity and the increased apoptosis contributed to the reduced cell proliferation phenotype observed in the RUNX1 KD group of THP-1 cells (Figure 2C)
Summary
Transcription factor RUNX1, known as AML1 or CBFA-2, plays a pivotal role in normal hematopoiesis. Current studies have found that RUNX1-ETO can cause abnormal cell differentiation, but the fusion protein itself is insufficient to develop into acute myeloid leukemia (AML) unless there are additional mutations (Nishida et al, 2006; Becker et al, 2008). These results were consistent with the predominant hypothesis on leukemogenesis, known as the “two-hit” model, which suggests that leukemia development requires the existence of a combination of two gene alterations (Knudson, 1971; Conway O’Brien and Steven, 2014). Our results pave the way for further exploration of the molecular mechanisms associated with dysregulated RUNX1 in leukemia
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