Abstract
Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.
Highlights
Leukemia is a severe clonal disease of the hematopoietic system characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow (Juliusson and Hough, 2016)
We further analyzed the RNA-seq data downloaded from the TCGA leukemia dataset, and the results showed that the ERG expression was significantly upregulated in Acute myeloid leukemia (AML) patients compared with normal tissues (Figure 1E)
The results showed that the overall survival had no significant difference between AML patients with high ERG levels and low ERG levels (Figure 1F), which my due to too few numbers of AML patients
Summary
Leukemia is a severe clonal disease of the hematopoietic system characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow (Juliusson and Hough, 2016). Leukemia is caused by genetic and epigenetic alterations in the regulatory processes associated with hematologic malignancies, including the inactivation of tumor suppressor genes and the activation of oncogenes (Cai and Levine, 2019). Acute myeloid leukemia (AML) is the most common type of severe hematological malignant tumor with clonal disorder, which is caused by the oncogenic transformation of myeloid progenitor cells and hematopoietic stem cells (Ferrara and Schiffer, 2013). There are other types of ERG alterations associated with AML, such as chromosomal translocation t(X;21)(q25–26; q22), which generates a fusion protein of two ETS family members, ELF4 and ERG (Moore et al, 2006). The high expression of ERG is closely associated with different types of hematological malignancies, affecting the overall and disease-free survival rates of patients (Tsuzuki et al, 2011). The roles of ERG in the pathogenesis of AML and the associated molecular mechanism remain unclear
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