Fujisaki H, Hara J, Takai K, Nakanishi K, Matsuda Y, Ohta H, Osugi Y, Tokimasa S, Taniike M, Hosoi G, Sako M, Okada S
Department of Pediatrics, Faculty of Medicine, Osaka University, Suita, Japan.
Exp Hematol. 1999 May;27(5):826-33. doi: 10.1016/s0301-472x(99)00008-9.
Morphophenotypic lineage switches occur in a small percentage of those with acute leukemia, and the underlying mechanisms are not clear. In this study, we attempted to induce a lineage switch in acute myelocytic leukemia (AML) with monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL) during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the transplanted myeloid cells were engrafted in SCID mice without cytokine administration, T-ALL developed in SCID mice treated with recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma-chain (TCR-gamma) gene revealed that this lineage switch resulted from the selection of the T-lineage subclone in SCID mice, which had expanded at onset. In addition, we found that the T-lineage and myeloid cells belonged to the distinct subclones, which were different in TCR-gamma gene rearrangements, but were derived from a common clone with an identical N-ras gene mutation for both subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage subclone failed to grow even in the presence of recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. These results suggested that the initial diagnostic T-lymphoid subclone, whose growth was dependent on these cytokines and the hematopoietic microenvironment, emerged from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic event(s) induced the myeloid subclone, which grew independently of these cytokines and the microenvironment.
形态表型谱系转换发生在一小部分急性白血病患者中，其潜在机制尚不清楚。在本研究中，我们试图在严重联合免疫缺陷（SCID）小鼠中诱导患有7号染色体单体的急性髓细胞白血病（AML）发生谱系转换，该AML在化疗期间其谱系已从急性T淋巴细胞白血病（T-ALL）转换而来。尽管在未给予细胞因子的情况下，移植的髓系细胞能在SCID小鼠中植入，但在用重组人粒细胞-巨噬细胞集落刺激因子或重组人白细胞介素3处理的SCID小鼠中发生了T-ALL。对重排的T细胞受体γ链（TCR-γ）基因的核苷酸序列分析表明，这种谱系转换是由于SCID小鼠中T谱系亚克隆的选择所致，该亚克隆在发病时已扩增。此外，我们发现T谱系和髓系细胞属于不同的亚克隆，它们在TCR-γ基因重排上不同，但源自一个具有相同N-ras基因突变的共同克隆。在体外培养中，只有髓系亚克隆生长；即使存在重组人粒细胞-巨噬细胞集落刺激因子或重组人白细胞介素3，T谱系亚克隆也无法生长。这些结果表明，最初诊断的T淋巴细胞亚克隆，其生长依赖于这些细胞因子和造血微环境，源自一个双潜能T淋巴细胞/髓系白血病干细胞，进一步的基因事件诱导了髓系亚克隆，该亚克隆的生长独立于这些细胞因子和微环境。
