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<p>Natural killer (NK) cells recognize and eliminate malignant cells through multiple receptor–ligand interactions. To uncover genetic determinants of the susceptibility of myeloid leukemia cells to NK cell cytotoxicity, we analyzed several genome-wide CRISPR screens. Among recurrent hits, the <i>BRCA1-associated protein 1</i> (<i>BAP1</i>) gene emerged as a key factor protecting K562 leukemic cells from NK cell-mediated killing. Using <i>BAP1</i> knockout (KO) models, we found that loss of BAP1 alone did not alter NK cell sensitivity. However, upon interferon-γ (IFN-γ) stimulation, <i>BAP1</i> KO K562 cells exhibited reduced HLA class I induction, triggered enhanced NK cell degranulation, and showed increased sensitivity to NK cell-mediated cytotoxicity compared with wild-type cells. Further experiments revealed that BAP1-deficient cells displayed reduced expression of the IFN-γ receptor 1 (IFN-γ-R1). <i>BAP1</i> knockdown across multiple myeloid leukemia cell lines selectively decreased HLA-E and IFN-γ-R1 expression in <i>ASXL1</i>-mutant backgrounds. These findings suggest that BAP1 may contribute to the regulation of IFN-γ responsiveness and immune evasion in myeloid leukemia.</p>

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BAP1 loss impairs IFN-γ signaling and enhances NK cell-mediated cytotoxicity in myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Chiara Badami,
  • Erna Islamagic,
  • Linnea Blomén,
  • Frida Svensson,
  • Theebiga Kathirkamanathan,
  • Kristoffer Hellstrand,
  • Elin Bernson,
  • Fredrik B. Thorén

摘要

Natural killer (NK) cells recognize and eliminate malignant cells through multiple receptor–ligand interactions. To uncover genetic determinants of the susceptibility of myeloid leukemia cells to NK cell cytotoxicity, we analyzed several genome-wide CRISPR screens. Among recurrent hits, the BRCA1-associated protein 1 (BAP1) gene emerged as a key factor protecting K562 leukemic cells from NK cell-mediated killing. Using BAP1 knockout (KO) models, we found that loss of BAP1 alone did not alter NK cell sensitivity. However, upon interferon-γ (IFN-γ) stimulation, BAP1 KO K562 cells exhibited reduced HLA class I induction, triggered enhanced NK cell degranulation, and showed increased sensitivity to NK cell-mediated cytotoxicity compared with wild-type cells. Further experiments revealed that BAP1-deficient cells displayed reduced expression of the IFN-γ receptor 1 (IFN-γ-R1). BAP1 knockdown across multiple myeloid leukemia cell lines selectively decreased HLA-E and IFN-γ-R1 expression in ASXL1-mutant backgrounds. These findings suggest that BAP1 may contribute to the regulation of IFN-γ responsiveness and immune evasion in myeloid leukemia.