Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.

中文翻译：

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浆细胞样树突状细胞扩张定义了RUNX1突变的急性髓细胞白血病的一个独特子集

浆细胞样树突状细胞（pDC）是主要的天然I型干扰素产生树突状细胞。pDC和pDC前体的肿瘤性扩增会导致弹塑性浆细胞样树突状细胞瘤（BPDCN），成熟的pDC的克隆性扩增已在慢性粒细胞单核细胞白血病（CMML）中进行了描述。pDC扩展在急性髓细胞性白血病（AML）中的作用研究很少。在这里，我们表征了具有pDC扩展（pDC-AML）的AML患者，我们在大约5％的AML中观察到了这种情况。pDC-AML通常具有跨谱系抗原表达，并且具有不良的危险分层，预后不良。RUNX1突变是pDC-AML中最常见的体细胞变异（> 70％），比没有PDC扩展的AML中更为常见。我们证明，pDC与pDC-AML中的白血病母细胞克隆相关，并起源于此。我们进一步证明，来自RUNX1突变的AML的白血病母细胞上调了pDC转录程序，使细胞朝着pDC分化和扩展方向发展。最后，在患者来源的异种移植模型中，针对CD123的靶向治疗药物tagraxofusp减轻了白血病负担，并消除了pDC。总之，pDC-AML的特征是RUNX1突变的频率很高，并且pDC转录程序的表达增加。CD123靶向是pDC-AML的潜在治疗方法。