Abstract
Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.
Highlights
CBFB is the beta subunit of heterodimeric core-binding transcription factor which master-regulates vital subsets of genes implicated in hematopoiesis and osteogenesis[1]
The additional knockdown of RUNX family genes augmented RUNX1 silencing-induced expression of CBFB and p53, which prompted us to investigate the possible interactions of CBFB with p53
We have found for the first time that CBFB transcription is modulated by RUNX family members, we have failed to find out any consensus RUNX-binding sequences (5′-TGTGGT-3′ or 5′-TGCGGT-3′) within the proximal promoter region of CBFB
Summary
The context-dependent oncogenic and oncosuppressive functions of RUNX family members (RUNX1, RUNX2 and RUNX3) have been well-described in multiple studies[1]. We have found the redundant functions of RUNX1, RUNX2 and RUNX3 in tumorigenesis and demonstrated that shRNA-mediated knockdown of RUNX1 in AML cells reciprocally up-regulates RUNX2 and RUNX3 expressions[5]. From these experiments, we have found RUNX1. Since the results obtained from our series of gene knockdown and overexpression experiments did not support the above-mentioned hypothesis, it is likely that there exists an alternative molecular mechanism behind the regulation of CBFB expression in AML cells. Our present study identified the novel molecular mechanism behind CBFB regulation and its indispensable roles in tumorigenesis, which provides an insight into understanding how AML cells could become resistant to RUNX1-inhibition therapy (Fig. 7). Our present study strongly suggests that an autonomous RUNX1-p53-CBFB regulatory triangle plays a vital role in the maintenance and the acquisition of chemo-resistance of AML cells, and potentially provides novel therapeutic targets for anti-leukemia strategy
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