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Immune evasion by oncogenic proteins of acute myeloid leukemia.

ABSTRACT: PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immunoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48.

SUBMITTER: Elias S

PROVIDER: S-EPMC3981677 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Immune evasion by oncogenic proteins of acute myeloid leukemia.

Elias Shlomo S Yamin Rachel R Golomb Lior L Tsukerman Pinchas P Stanietsky-Kaynan Noah N Ben-Yehuda Dina D Mandelboim Ofer O

Blood 20140121 10

PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (H ...[more]

PMID: 24449212

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Project description:Background Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Given the high relapse rate, more effective treatments are needed to improve clinical outcomes. We previously demonstrated that heme oxygenase 1 (HO1) is overexpressed in AML, while the functional roles of HO1 remain unclear. Methods Bioinformatics analysis and flow cytometry were conducted to assess the association between HO1 levels and immune cells or immune checkpoint/ligand molecules in AML patients. Primary natural killer (NK) cells were purified and subsequently co-cultured in vitro with transduced AML cells to determine the effects of HO1 expression on NK cell functions. AML mice models were established to investigate the effects of HO1 expression on cytotoxic effects of NK cells in vivo. The molecular mechanism was studied by flow cytometry, quantitative real-time PCR (qRT-PCR), western blotting, and immunoprecipitation. Results Bioinformatics analysis indicated a correlation between HO1 expression and the AML immune microenvironment. The present study findings indicated that HO1 specifically downregulates the expression of CD48, a ligand of the NK cell-activating receptor 2B4, thus decreasing the cytotoxic effect of NK cells. HO1 overexpression promoted tumor growth and inhibited the cytotoxic effect of NK cells in the AML mice model. Mechanistic investigations found that HO1 directly interacted with Sirt1 and increased its expression and deacetylase activity. With the overexpression of HO1, increased Sirt1 in AML cells enabled histone H3K27 deacetylation to suppress CD48 transcription and expression. Administration of Sirt1 inhibitor restored the expression of CD48. Conclusions Collectively, HO1 promotes NK cell dysfunction in AML. Therefore, restoring NK cell function by inhibiting HO1 activity is a potential immunotherapeutic approach against AML. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03589-z.

Dataset Information

Immune evasion by oncogenic proteins of acute myeloid leukemia.

Publications

Immune evasion by oncogenic proteins of acute myeloid leukemia.

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