Disruption of normal differentiation is an important link in tumorigenesis, but understanding the molecular mechanisms underlying this process is still limited. Acute myeloid leukemia (AML) is characterized by an accumulation of immature myeloid precursor cells in the bone marrow, which has been extensively used as a model for studying genetic/epigenetic regulation of differentiation and cancer progression. Intensive studies using cultured AML cells and animal models have identified well-known aberrant transcription factors, such as CEBPA, RARα, RUNX1, PU.1, GATA2, etc1. Consequently, pharmacological restoration of their function represents a promising therapeutic strategy. Noteworthily, all-trans retinoic acid was shown to be capable of inducing the terminal differentiation of immature leukemic promyelocytes, and firstly used clinically in 19882. Thus, identifying new molecular mechanisms that control myeloid differentiation is fundamental in developing novel anti-leukemic therapies.

In a recent issue of Journal of Clinical Investigation, Meritxell and colleagues have systematically elucidated the role of CEBPA-CEBPG pathway in myeloid differentiation3. The authors found in the gene expression profile analysis that CEBPG mRNA was significantly upregulated in a small subset of AML patients with CEBPA hypermethylation/silencing (8/526). They further demonstrated in a CEBPA conditional knockout mice model that ablation of CEBPA led to upregulation of CEBPG in early stem/progenitor cells. CEBPA could bind to CEBPG proximal promoter and downregulate CEBPG expression by affecting E2F1 transcriptional activity. Furthermore, they showed that CEBPG was downregulated during neutrophilic differentiation in a 32D/G-CSF–R murine cell line model, whereas overexpression of CEBPG blocked granulocytic differentiation. Conversely, inhibition of CEBPG by specific shRNA in vitro or in vivo restored granulocytic differentiation in a CEBPA-knockout early hematopoietic stem/progenitor cells. Intriguingly, the authors found that the DNA demethylating agent 5-aza-2'-deoxycitidine (decitabine) restored the CEBPA-CEBPG balance and induced myeloid differentiation in CEBPA-silenced primary AML blasts. Thus, the authors concluded that targeting the CEBPA-CEBPG pathway represented a novel therapeutic approach in a particular subtype of AML.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD