Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Ann Hematol. 2011 Sep;90(9):1047-58. doi: 10.1007/s00277-011-1231-2. Epub 2011 Apr 26.
Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation during leukemogenesis are not clear. We compared the frequency of cells with immunophenotype of myeloid DC (mDC: Lin(-), HLA-DR(+), CD11c(+), CD86(+)) and plasmacytoid DC (pDC: Lin(-), HLA-DR(+), CD123(+), CD86(+)) in diagnostic samples of 47 FLT3-ITD(-) and 40 FLT3-ITD(+) AML patients. The majority of ITD(+) AML samples showed high frequencies of mDCs or pDCs, with significantly decreased HLA-DR expression compared with DCs detectable in ITD(-) AML samples. Interestingly, mDCs and pDCs sorted out from ITD(+) AML samples contained the ITD insert revealing their leukemic origin and, upon ex vivo culture with cytokines, they acquired DC morphology. Notably, mDC/pDCs were detectable concurrently with single lineage mDCs and pDCs in all ITD(+) AML (n = 11) and ITD(-) AML (n = 12) samples analyzed for mixed lineage DCs (Lin(-), HLA-DR(+), CD11c(+), CD123(+)). ITD(+) AML mDCs/pDCs could be only partially activated with CD40L and CpG for production of IFN-α, TNF-α, and IL-1α, which may affect the anti-leukemia immune surveillance in the course of disease progression.
约 30%的急性髓系白血病（AML）患者存在 FMS 样酪氨酸激酶 3（FLT3）基因内部串联重复（ITD）突变。FLT3-ITD 已知可驱动造血干细胞向 FLT3 配体非依赖性生长，但在白血病发生过程中对树突状细胞（DC）分化的影响尚不清楚。我们比较了 47 例 FLT3-ITD(-)和 40 例 FLT3-ITD(+)AML 患者诊断样本中具有髓样 DC（mDC：Lin(-)，HLA-DR(+)，CD11c(+)，CD86(+)）和浆细胞样 DC（pDC：Lin(-)，HLA-DR(+)，CD123(+)，CD86(+)）表型的细胞频率。大多数 ITD(+)AML 样本显示 mDC 或 pDC 的频率较高，与可检测到的 ITD(-)AML 样本中的 DC 相比，其 HLA-DR 表达明显降低。有趣的是，从 ITD(+)AML 样本中分选的 mDC 和 pDC 含有 ITD 插入，表明其白血病起源，并且在体外与细胞因子培养后获得 DC 形态。值得注意的是，在所有分析的 ITD(+)AML（n=11）和 ITD(-)AML（n=12）样本中，均可同时检测到 mDC/pDC 和单谱系 mDC 和 pDC，用于检测混合谱系 DC（Lin(-)，HLA-DR(+)，CD11c(+)，CD123(+)）。ITD(+)AML mDC/pDC 只能部分被 CD40L 和 CpG 激活，以产生 IFN-α、TNF-α 和 IL-1α，这可能会影响疾病进展过程中的抗白血病免疫监测。
