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<p>Mature plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML) is a distinct entity with poor prognosis. Yet, the mechanisms underlying the immune evasion and aberrant pDC expansion remain poorly understood. We performed multi-omic profiling of 18 pDC-AML cases, along with 207 non-pDC-AML and 16 BPDCN cases as controls. Single-cell RNA-seq and proteomic analyses demonstrated that pDC-AML leukemia stem cells exhibited unfolded protein response activation, particularly the IRE1α-XBP1 axis, which preceded the acquisition of the pDC maturation program. Supporting this, pharmacological induction of endoplasmic reticulum stress in myeloid cells upregulated <i>BCL11A</i>, the master transcription factor in pDC differentiation, and induced a pDC immunophenotype (CD123<sup>+</sup>BDCA2<sup>+</sup>). Importantly, pDC-AML-derived pDCs exhibited functional impairment, including compromised antigen-presenting pathways and reduced interactions between pDCs and CD8<sup>+</sup> T cells. scTCR-seq analysis revealed significantly restricted T-cell clonal expansion in the pDC-AML bone marrow microenvironment, which correlated with leukemic burden and reversed upon clinical remission. Notably, allogeneic hematopoietic stem cell transplantation (HSCT) significantly improved overall and progression-free survival, abrogating the prognostic disadvantage relative to non-pDC-AML. Collectively, these findings establish impaired anti-leukemia immunity as a hallmark of pDC-AML, support early HSCT as a clinical priority, and identify ER-stressed pDCs as a potential novel therapeutic target.</p><p></p>

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Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune suppression in acute myeloid leukemia

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Xingcheng Yang,
  • Juan Peng,
  • Xia Mao,
  • Lei Zhang,
  • Shaolong He,
  • Chunyan Wang,
  • Yicheng Zhang,
  • Yuting Tang,
  • Jue Wang,
  • Jia Wei

摘要

Mature plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML) is a distinct entity with poor prognosis. Yet, the mechanisms underlying the immune evasion and aberrant pDC expansion remain poorly understood. We performed multi-omic profiling of 18 pDC-AML cases, along with 207 non-pDC-AML and 16 BPDCN cases as controls. Single-cell RNA-seq and proteomic analyses demonstrated that pDC-AML leukemia stem cells exhibited unfolded protein response activation, particularly the IRE1α-XBP1 axis, which preceded the acquisition of the pDC maturation program. Supporting this, pharmacological induction of endoplasmic reticulum stress in myeloid cells upregulated BCL11A, the master transcription factor in pDC differentiation, and induced a pDC immunophenotype (CD123+BDCA2+). Importantly, pDC-AML-derived pDCs exhibited functional impairment, including compromised antigen-presenting pathways and reduced interactions between pDCs and CD8+ T cells. scTCR-seq analysis revealed significantly restricted T-cell clonal expansion in the pDC-AML bone marrow microenvironment, which correlated with leukemic burden and reversed upon clinical remission. Notably, allogeneic hematopoietic stem cell transplantation (HSCT) significantly improved overall and progression-free survival, abrogating the prognostic disadvantage relative to non-pDC-AML. Collectively, these findings establish impaired anti-leukemia immunity as a hallmark of pDC-AML, support early HSCT as a clinical priority, and identify ER-stressed pDCs as a potential novel therapeutic target.