Griffiths S D, Healy L E, Ford A M, Bennett C A, Voncken J W, Heisterkamp N, Groffen J, Greaves M F
Leukaemia Research Fund Centre, Chester Beatty Laboratories, London, UK.
Oncogene. 1992 Jul;7(7):1391-9.
The clonal and immunophenotypic characteristics of blood leukemic cells from BCR/ABL p190 transgenic mice were investigated. All cell populations evaluated in vivo and in vitro had B-lymphocyte progenitor immunophenotypes. Immunoglobulin (JH) rearrangement patterns provided evidence for clonal diversification at different sites in vivo. Multiple clones were established in vitro from two of these mice (nos. 730 and 753). These cells expressed BCR/ABL p190 protein tyrosine kinase (PTK) and were highly malignant on transfer to secondary recipients. Cells independently cloned in vitro shared identical immunophenotypes and clonal IgH rearrangements, but these were distinct from those of the dominant clones in the mouse from which they were derived. Nevertheless, in vitro clones from mouse no. 753 had an abnormal karyotype (chromosome 14 trisomy) in common with the dominant clone in blood, providing evidence for a hierarchy or clonal selection in vivo and in vitro. Two sets of in vitro clones proliferated independently of exogenous growth factors and stroma and released autocrine interleukin 7 growth factor activity. These data provide evidence for rapid divergent clonal evolution and selection of B-cell progenitors initiated by BCR/ABL p190, followed by other, secondary genetic events mirroring similar changes in the equivalent, highly malignant human leukemia Philadelphia (Ph)-positive/B-precursor acute lymphoblastic leukemia (ALL).
对来自BCR/ABL p190转基因小鼠的血液白血病细胞的克隆和免疫表型特征进行了研究。体内和体外评估的所有细胞群体均具有B淋巴细胞祖细胞免疫表型。免疫球蛋白（JH）重排模式为体内不同部位的克隆多样化提供了证据。从其中两只小鼠（730号和753号）体外建立了多个克隆。这些细胞表达BCR/ABL p190蛋白酪氨酸激酶（PTK），转移至二级受体时具有高度恶性。体外独立克隆的细胞具有相同的免疫表型和克隆性IgH重排，但与它们所源自的小鼠中的优势克隆不同。然而，753号小鼠的体外克隆与血液中的优势克隆具有共同的异常核型（14号染色体三体），为体内和体外的层次结构或克隆选择提供了证据。两组体外克隆独立于外源性生长因子和基质增殖，并释放自分泌白细胞介素7生长因子活性。这些数据为BCR/ABL p190引发的B细胞祖细胞的快速分化克隆进化和选择提供了证据，随后是其他继发性遗传事件，反映了等效的高度恶性人类白血病费城（Ph）阳性/B前体急性淋巴细胞白血病（ALL）中的类似变化。
