LncRNA USP30-AS1 promotes the survival of acute myeloid leukemia cells by cis-regulating USP30 and ANKRD13A

AbstractAcute myeloid leukemia (AML) is a malignant tumor derived from leukemia stem cells, with complicated pathogenesis. LncRNAs play an important role in tumors genesis and progression. According to results from bioinformatics analysis, lncRNA USP30-AS1 is highly expressed in AML and both the high expression of USP30-AS1 and low methylation level at Cg03124318 locus of USP30-AS1 gene promoter are associated with poor prognosis of AML. This study knocked down and overexpressed USP30-AS1 to determine the roles in AML cell lines. High-throughput sequencing was performed to explore the genes regulated by USP30-AS1. Results showed that USP30-AS1 promoted AML cell viability and inhibited apoptosis. Genes regulated by USP30-AS1 are mainly related to genetic regulation and immune system. Among them, USP30 and ANKRD13A genes are close to USP30-AS1 gene in chromosome. Knockdown of USP30, but not ANKRD13A, abolished the cancer-promoting effects of USP30-AS1. ANKRD13A recognizes Lys-63-linked polyubiquitin chain in HLA-I. USP30-AS1 induced HLA-I internalization from the cell membrane by up-regulating ANKRD13A, which might induce the immune escape of AML cells. ChIP analysis revealed that the regulatory effects of USP30-AS1 on USP30 and ANKRD13A are associated with H3K4me3 and H3K27Ac. In summary, USP30-AS1 probably promotes AML cell survival by cis-regulating USP30 and ANKRD13A.

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Rapamycin downregulates NKG2D ligands in acute myeloid leukemia cells via an activation of the STAT3 pathway: a potential mechanism for rapamycin-induced immune escape in leukemia

Translational Cancer Research ◽

10.21037/tcr.2019.03.01 ◽

2019 ◽

Vol 8 (2) ◽

pp. 473-482

Author(s):

Zhichao Zhu ◽

Yu Bai ◽

Xuzhang Lu ◽

Jun Ding ◽

Chunjian Qi

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Immune Escape ◽

Leukemia Cells ◽

Potential Mechanism ◽

Stat3 Pathway ◽

Nkg2d Ligands ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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Pivotal role of DPYSL2A in KLF4-mediated monocytic differentiation of acute myeloid leukemia cells

Scientific Reports ◽

10.1038/s41598-020-76951-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mina Noura ◽

Ken Morita ◽

Hiroki Kiyose ◽

Hidemasa Matsuo ◽

Yoko Nishinaka-Arai ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Patterns ◽

Terminal Differentiation ◽

Gene Promoter ◽

Leukemia Cells ◽

Monocytic Differentiation ◽

Acute Myeloid Leukemia Cells ◽

Underlying Mechanisms ◽

Acute Myeloid

AbstractAlthough the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML.

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