Valent P, Spanblöchl E, Bankl H C, Sperr W R, Marosi C, Pirc-Danoewinata H, Virgolini I, Eichler H G, Agis H, Sillaber C
Department of Internal Medicine, University of Vienna, Austria.
Blood. 1994 Dec 15;84(12):4322-32.
Autonomous, factor-independent growth and differentiation of malignant cells in preleukemic and leukemic disease states is a well-recognized phenomenon and is often associated with a poor prognosis. Mast cells are distinct hematopoietic cells and express a unique profile of antigens. Growth and differentiation of normal mast cells is dependent on mast cell growth factor (MGF), the ligand of the c-kit protooncogene product. In this study, we screened for mast cell-lineage involvement in 52 patients suffering from myeloid leukemias, myelodysplastic syndromes (MDS), systemic mastocytosis, or other diseases by probing for mast cell-related molecules (c-kit, tryptase, histamine, and MGF) and by analyzing kit ligand/MGF-independent growth of mast cells in long-term suspension culture. Of the 52 patients tested, 2 patients with refractory anemia with excess of blast cells in transformation and 1 patient suffering from chronic myeloid leukemia blast crisis (CML-BC) were diagnosed as mastocytic disease. These patients were characterized by complex chromosomal abnormalities, splenomegaly, high percentages of circulating metachromatic cells (5% to 25%), high levels of cellular tryptase (> 10 ng/10(5) peripheral blood mononuclear cells/mL) and a tryptase/histamine (ng:ng) ratio greater than 1. The metachromatic cells expressed the mast-cell-related surface antigen c-kit, but not basophil-related antigens (CD11b, CDw17). Furthermore, in these 3 patients, spontaneous, MGF-independent growth of mast cells along with spontaneous synthesis of tryptase was demonstrable in long-term culture. No autocrine production, paracrine production, or overproduction of MGF was found. The spontaneous growth of mast cells could neither be abbrogated by addition of monoclonal antibodies (MoAbs) to c-kit nor by MoAbs against MGF (< 5% inhibition), whereas factor (MGF)-dependent differentiation of mast cells in these patients could be abbrogated by MoAbs to c-kit or MoAbs to MGF (> 70% inhibition, P < .001). In addition, serum MGF levels in these patients were within the normal range and MGF could not be detected in cell-free culture supernatants. All 3 patients showed rapid progression of disease and had a survival time of less than 1 year. In conclusion, we describe a unique form of transformation in MDS and CML-BC characterized by mast cell lineage involvement and factor-independent differentiation of mast cells. This form of leukemic transformation has to be delineated from chronic myeloid leukemia with basophilia or basophil crisis, from primary mast cell leukemia, and from monocytic leukemias and myelodysplastic disorders associated with basophilia.
在白血病前期和白血病状态下，恶性细胞的自主、因子非依赖性生长和分化是一种公认的现象，且常与预后不良相关。肥大细胞是独特的造血细胞，表达独特的抗原谱。正常肥大细胞的生长和分化依赖于肥大细胞生长因子（MGF），即c-kit原癌基因产物的配体。在本研究中，我们通过检测肥大细胞相关分子（c-kit、类胰蛋白酶、组胺和MGF）以及分析长期悬浮培养中肥大细胞的kit配体/MGF非依赖性生长，来筛查52例患有髓系白血病、骨髓增生异常综合征（MDS）、系统性肥大细胞增多症或其他疾病的患者中是否有肥大细胞系受累情况。在检测的52例患者中，2例转化型原始细胞增多的难治性贫血患者和1例慢性髓系白血病急变期（CML-BC）患者被诊断为肥大细胞疾病。这些患者的特征为复杂的染色体异常、脾肿大、循环中异染性细胞百分比高（5%至25%）、细胞类胰蛋白酶水平高（>10 ng/10⁵外周血单个核细胞/mL）以及类胰蛋白酶/组胺（ng:ng）比值大于1。异染性细胞表达肥大细胞相关表面抗原c-kit，但不表达嗜碱性粒细胞相关抗原（CD11b、CDw17）。此外，在这3例患者中，长期培养显示肥大细胞有自发的、MGF非依赖性生长以及类胰蛋白酶的自发合成。未发现MGF的自分泌产生、旁分泌产生或过量产生。肥大细胞的自发生长既不能通过添加针对c-kit的单克隆抗体（MoAbs）来消除，也不能通过针对MGF的MoAbs来消除（抑制率<5%），而这些患者中肥大细胞的因子（MGF）依赖性分化可被针对c-kit的MoAbs或针对MGF的MoAbs消除（抑制率>70%，P<.001）。此外，这些患者的血清MGF水平在正常范围内，且在无细胞培养上清液中未检测到MGF。所有3例患者疾病进展迅速，生存时间均不足1年。总之，我们描述了一种在MDS和CML-BC中独特的转化形式，其特征为肥大细胞系受累以及肥大细胞的因子非依赖性分化。这种白血病转化形式必须与伴有嗜碱性粒细胞增多或嗜碱性粒细胞危象的慢性髓系白血病、原发性肥大细胞白血病以及与嗜碱性粒细胞增多相关的单核细胞白血病和骨髓增生异常疾病相区分。
