Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune...

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.