Costello R, Mallet F, Chambost H, Sainty D, Arnoulet C, Gastaut J A, Olive D
Immunologie des Tumeurs, Département d'Hématologie, Institut Paoli-Calmettes, Université de Méditerranée, Marseille, France.
Leukemia. 1999 Oct;13(10):1513-8. doi: 10.1038/sj.leu.2401519.
Minimally differentiated acute myeloid leukemia (AML-M0) is a rare FAB subtype (2-3% of AMLs) of poor prognosis. The aim of our study was to characterize AML-M0 expression and regulation of adhesion/costimulatory molecule involved in immune recognition, to test blast in vitro immunogenicity, and to determine the percentage of leukemia progenitor cells. Here, we demonstrate that alloimmune recognition of AML-M0 in primary mixed lymphocyte reaction, as evaluated by IL-2 secretion of responding T cells, is reduced in comparison with more differentiated subtypes (128 +/- 95 pg/ml vs304 +/- 159 pg/ml, P < 0.05). These data are in line with low blast cell expression of major histocompatibility complex (MHC) class II DR molecules, and of the CD28 ligand B7-2, which plays an important role in AML immune recognition. Adhesion/costimulatory molecules were up-regulated by leukemic cell stimulation via CD40, and, although less efficiently, by gamma-IFN; both stimuli improved blast cell immunogenicity. We also demonstrate that AML-M0 have a very high percentage (40% +/- 30) of CD34+/CD38- leukemic clonogenic precursors in comparison with more differentiated AMLs (2.5% +/- 2) or non-leukemic CD34+hematopoietic precursors (1.8% +/- 0.8). Since the presence of a leukemic cell population at an early differentiation stage has been identified as a poor prognostic factor, we conclude that the high frequency of CD34+/CD38- blasts in AML-M0 may converge with already identified poor prognosis factors such as chemotherapy resistance and cytogenetic abnormalities. The clinical implications of AML-M0 impaired in vitroimmunogenicity and a high percentage of CD34+/CD38- blasts will require comparative analysis of additional patients. The increased immunogenicity of blast cells after CD40 triggering provide interesting clues for AML-M0 immunotherapy, that have to be confirmed with an in vivo leukemia model in mice.
微分化急性髓系白血病（AML-M0）是一种罕见的FAB亚型（占AML的2%-3%），预后较差。我们研究的目的是对参与免疫识别的AML-M0黏附/共刺激分子的表达和调控进行表征，检测原始细胞的体外免疫原性，并确定白血病祖细胞的百分比。在此，我们证明，在原发性混合淋巴细胞反应中，通过反应性T细胞分泌的IL-2评估，与分化程度更高的亚型相比，AML-M0的同种异体免疫识别降低（128±95 pg/ml对304±159 pg/ml，P<0.05）。这些数据与主要组织相容性复合体（MHC）II类DR分子以及在AML免疫识别中起重要作用的CD28配体B7-2的低原始细胞表达一致。黏附/共刺激分子通过CD40刺激白血病细胞上调，并且尽管效率较低，但通过γ-干扰素也能上调；两种刺激均改善了原始细胞的免疫原性。我们还证明，与分化程度更高的AML（2.5%±2）或非白血病CD34+造血前体（1.8%±0.8）相比，AML-M0具有非常高比例（40%±30）的CD34+/CD38-白血病克隆形成前体。由于已确定早期分化阶段白血病细胞群的存在是一个不良预后因素，我们得出结论，AML-M0中CD34+/CD38-原始细胞的高频率可能与已确定的不良预后因素如化疗耐药和细胞遗传学异常共同作用。AML-M0体外免疫原性受损和高比例CD34+/CD38-原始细胞的临床意义需要对更多患者进行比较分析。CD40触发后原始细胞免疫原性的增加为AML-M0免疫治疗提供了有趣的线索，这必须在小鼠体内白血病模型中得到证实。
