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<p>Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. <i>RUNX1</i> mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a <i>RUNX1</i> frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous <i>RUNX1</i> frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of <i>RUNX1</i>-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that <i>RUNX1</i> frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with <i>RUNX1</i>-mutated AML.</p><p></p>

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A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Nadine E. Struckman,
  • Georgia Koutsoumpli,
  • Rob C. M. de Jong,
  • Dyantha I. van der Lee,
  • Dennis F. G. Remst,
  • Sophie-Anne I. Smith,
  • M. Willy Honders,
  • Renate S. Hagedoorn,
  • Arnoud H. de Ru,
  • Masashi Matsuda,
  • Fumihiko Ishikawa,
  • Tamar Tak,
  • Peter J. M. Valk,
  • Mirjam H. M. Heemskerk,
  • Peter A. van Veelen,
  • J. H. Frederik Falkenburg,
  • Marieke Griffioen

摘要

Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. RUNX1 mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of RUNX1-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with RUNX1-mutated AML.