Scott A A, Head D R, Kopecky K J, Appelbaum F R, Theil K S, Grever M R, Chen I M, Whittaker M H, Griffith B B, Licht J D
University of New Mexico (UNM) School of Medicine, Department of Pathology, Albuquerque.
Blood. 1994 Jul 1;84(1):244-55.
We have identified and characterized a previously unrecognized form of acute leukemia that shares features of both myeloid and natural killer (NK) cells. From a consecutive series of 350 cases of adult de novo acute myeloid leukemia (AML), we identified 20 cases (6%) with a unique immunophenotype: CD33+, CD56+, CD11a+, CD13lo, CD15lo, CD34+/-, HLA-DR-, CD16-. Multicolor flow cytometric assays confirmed the coexpression of myeloid (CD33, CD13, CD15) and NK cell-associated (CD56) antigens in each case, whereas reverse transcription polymerase chain reaction (RT-PCR) assays confirmed the identity of CD56 (neural cell adhesion molecule) in leukemic blasts. Although two cases expressed CD4, no case expressed CD2, CD3, or CD8 and no case showed clonal rearrangement of genes encoding the T-cell receptor (TCR beta, gamma, delta). Leukemic blasts in the majority of cases shared unique morphologic features (deeply invaginated nuclear membranes, scant cytoplasm with fine azurophilic granularity, and finely granular Sudan black B and myeloperoxidase cytochemical reactivity) that were remarkably similar to those of acute promyelocytic leukemia (APL); particularly the microgranular variant (FAB AML-M3v). However, all 20 cases lacked the t(15;17) and 17 cases tested lacked the promyelocytic/retinoic acid receptor alpha (RAR alpha) fusion transcript in RT-PCR assays; 12 cases had 46,XX or 46,XY karyotypes, whereas 2 cases had abnormalities of chromosome 17q: 1 with del(17)(q25) and the other with t(11;17)(q23;q21) and the promyelocytic leukemia zinc finger/RAR alpha fusion transcript. All cases tested (6/20), including the case with t(11;17), failed to differentiate in vitro in response to all-trans retinoic acid (ATRA), suggesting that these cases may account for some APLs that have not shown a clinical response to ATRA. Four of 6 cases tested showed functional NK cell-mediated cytotoxicity, suggesting a relationship between these unique CD33+, CD56+, CD16- acute leukemias and normal CD56+, CD16- NK precursor cells. Using a combination of panning and multiparameter flow cytometric sorting, we identified a normal CD56+, CD33+, CD16- counterpart cell at a frequency of 1% to 2% in the peripheral blood of healthy individuals. Our studies suggest that this form of acute leukemia may arise from transformation of a precursor cell common to both the myeloid and NK cell lineages; thus we propose the designation myeloid/NK acute leukemia. Recognition of this new leukemic entity will be important in distinguishing these ATRA-nonresponsive cases from ATRA-responsive true APL.
我们已经识别并鉴定出一种先前未被认识的急性白血病形式，它兼具髓系细胞和自然杀伤（NK）细胞的特征。在连续的350例成人原发性急性髓系白血病（AML）病例中，我们识别出20例（6%）具有独特免疫表型的病例：CD33+、CD56+、CD11a+、CD13lo、CD15lo、CD34+/-、HLA-DR-、CD16-。多色流式细胞术检测证实，每例病例中均存在髓系（CD33、CD13、CD15）和NK细胞相关（CD56）抗原的共表达，而逆转录聚合酶链反应（RT-PCR）检测证实白血病原始细胞中CD56（神经细胞黏附分子）的一致性。尽管有2例表达CD4，但无一例表达CD2、CD3或CD8，也没有病例显示编码T细胞受体（TCRβ、γ、δ）的基因发生克隆重排。大多数病例中的白血病原始细胞具有独特的形态学特征（核膜深陷、胞质稀少且有细小嗜天青颗粒、苏丹黑B和髓过氧化物酶细胞化学反应呈细颗粒状），与急性早幼粒细胞白血病（APL）极为相似；尤其是微颗粒变异型（FAB AML-M3v）。然而，所有20例病例均缺乏t(15;17)，且17例检测病例在RT-PCR检测中缺乏早幼粒细胞/维甲酸受体α（RARα）融合转录本；12例具有46,XX或46,XY核型，而2例存在17号染色体异常：1例为del(17)(q25)，另1例为t(11;17)(q23;q21)及早幼粒细胞白血病锌指蛋白/RARα融合转录本。所有检测病例（6/20），包括伴有t(11;17)的病例，在体外对全反式维甲酸（ATRA）均无反应，提示这些病例可能是部分对ATRA无临床反应的APL的病因。6例检测病例中有4例显示功能性NK细胞介导的细胞毒性，提示这些独特的CD33+、CD56+、CD16-急性白血病与正常CD56+、CD16-NK前体细胞之间存在关联。通过淘选和多参数流式细胞术分选相结合的方法，我们在健康个体外周血中以1%至2%的频率识别出一种正常的CD56+、CD33+、CD16-对应细胞。我们的研究提示，这种急性白血病形式可能源于髓系和NK细胞谱系共同的前体细胞的转化；因此我们提议将其命名为髓系/NK急性白血病。识别这种新的白血病实体对于区分这些对ATRA无反应的病例与对ATRA有反应的真性APL具有重要意义。
