Immune evasion by oncogenic proteins of acute myeloid leukemia.
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.
The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel;
Shlomo
S
Elias
Rachel
R
Yamin
Lior
L
Golomb
Pinchas
P
Tsukerman
Noah
N
Stanietsky-Kaynan
Dina
D
Ben-Yehuda
Ofer
O
Mandelboim
D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D000071178:CD48 Antigen; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology*
C107844:AML1-ETO fusion protein, human; D015703:Antigens, CD; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D006655:Histone Deacetylases