Falini Brunangelo, Martelli Maria Paola, Mecucci Cristina, Liso Arcangelo, Bolli Niccolò, Bigerna Barbara, Pucciarini Alessandra, Pileri Stefano, Meloni Giovanna, Martelli Massimo F, Haferlach Torsten, Schnittger Susanne
Institute of Hematology, University of Perugia, Perugia, Italy.
Haematologica. 2008 May;93(5):775-9. doi: 10.3324/haematol.12225. Epub 2008 Mar 26.
We investigated the NPM1 mutation status or subcellular expression of NPM protein (nuclear vs. aberrant cytoplasmic) at diagnosis and relapse in 125 patients with acute myeloid leukemia from Italy and Germany. All 52 patients with acute myeloidleukemia carrying at diagnosis mutated or cytoplasmic NPM (NPMc(+) acute myeloid leukemia) retained this feature at relapse. Notably, cytoplasmic mutated NPM has now been retained for eight years in a xenotransplant model of NPMc(+) acute myeloid leukemia in immunodeficient mice. None of 73 acute myeloid leukemia patients carrying at diagnosis wild-type NPM1 gene or showing at immunohistochemistry nucleus-restricted expression of nucleophosmin (NPMc(-) acute myeloid leukemia), which is predictive of NPM1 gene in germline configuration, acquired cytoplasmic mutated NPM at relapse. This finding further confirms that NPMc(+) acute myeloid leukemia represents a primary event rather than a transformation stage of NPMc(-) acute myeloid leukemia. The stability of cytoplasmic mutated NPM in patients with acute myeloid leukemia, even at relapse in extramedullary sites, and in a xenotransplant model, suggest this event is crucial for leukemogenesis and represents the rationale for monitoring minimal residual disease and molecular targeted therapy in NPMc(+) acute myeloid leukemia.
我们调查了来自意大利和德国的125例急性髓系白血病患者在诊断和复发时的NPM1突变状态或NPM蛋白的亚细胞表达情况（核型与异常胞质型）。所有52例在诊断时携带突变型或胞质型NPM的急性髓系白血病患者（NPMc(+)急性髓系白血病）在复发时仍保留这一特征。值得注意的是，在免疫缺陷小鼠的NPMc(+)急性髓系白血病异种移植模型中，胞质突变型NPM已保留了八年。73例在诊断时携带野生型NPM1基因或免疫组化显示核仁素呈核限制性表达的急性髓系白血病患者（NPMc(-)急性髓系白血病，提示NPM1基因呈种系构型），在复发时均未获得胞质突变型NPM。这一发现进一步证实，NPMc(+)急性髓系白血病代表一个原发性事件，而非NPMc(-)急性髓系白血病的转化阶段。急性髓系白血病患者中胞质突变型NPM的稳定性，即使在髓外部位复发时以及在异种移植模型中依然存在，提示这一事件对白血病发生至关重要，也是监测NPMc(+)急性髓系白血病微小残留病和分子靶向治疗的理论依据。
