Abstract
Acute erythroleukemia (AEL) is an infrequent subtype of acute myeloid leukemia (AML) with worse prognosis. Though the last decade has seen major advances in the novel features and genomic landscape in AEL, there is still a lack of specific therapeutic targets and effective treatment approaches for this disease. Here, we found a novel oncogene KEL that specifically and aberrantly expressed in patients with AEL. In this study, we demonstrated that KEL promoted cell proliferation and the downregulation of KEL reversed drug resistance in AEL cells to JQ1. Our findings suggested that KEL contributed to gain of H3K27 acetylation and promoted erythroid differentiation induced by GATA1. Additionally, GATA1 and TAL1 as cotranscription factors (TFs) modulated the expression of KEL. Maintaining cell viability and differentiation, KEL also played parts in the immune evasion of tumor cells. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, offering promising therapeutic target to broaden the treatment options.
Highlights
Leukemia is often originated from certain phases of hematopoietic cells and shows disorders of differentiation
We found that Kell blood group (KEL) was highly expressed in M6 patients compared with other subtype of acute myeloid leukemia (AML) patients (Figures 1(a) and 1(b))
RT-qPCR and agarose gel electrophoresis analysis demonstrated that, consistent with The Cancer Genome Atlas (TCGA) database, patients with AML-M6 showed higher level of KEL mRNA compared with non-M6 patients and healthy donors (Figure 1(e) and Fig. S1B)
Summary
Leukemia is often originated from certain phases of hematopoietic cells and shows disorders of differentiation. Acute erythroleukemia (AEL) is named as AML-M6, an invasive form of an infrequent subtype of acute myeloid leukemia (AML) based on the French–American–British (FAB) classification This disease was first described by Copelli in 1912 [1]. Regulates its own transcriptional activity through posttranslational modification, such as acetylation and phosphorylation, GATA1 can form dynamic complex with various TFs to selectively regulate downstream genes and participate in erythroid differentiation [8]. As key erythroid TFs, GATA1 and TAL1, cooperate, along with other proteins, to regulate the process of hematopoiesis and differentiation. It has been reported that certain erythroid cell-specific genes are activated by a complex formed by GATA1 and TAL1 [11]. Recent studies of histone modification have assisted us to better understand the internal regulation of TFs. Controlling gene expression and defining cellular identities, histone modification represents a central oncogenic pathway and drug resistance in AML [12]. For the first time, that KEL-mediated epigenetic alterations contribute to JQ1 resistance and provided new insights into the pathogenesis and treatment of AEL
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