The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.
The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.
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DOI：
10.1084/jem.189.9.1399
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发表时间：
1999-05-03
期刊：
影响因子：
--
通讯作者：
Van Etten RA
中科院分区：
文献类型：
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作者：
Li S;Ilaria RL Jr;Million RP;Daley GQ;Van Etten RA
费城染色体（Ph）易位的产物，BCR/ABL癌基因，存在于三种主要形式（P190，P210和P230 BCR/ABL），发现在不同形式的Ph阳性白血病，这表明三种蛋白质具有不同的白血病活性。我们已经直接比较了酪氨酸激酶活性，体外转化性能，并在体内白血病活性的P190，P210，和P230形式的BCR/ABL.P230表现出较低的内在酪氨酸激酶活性比P210和P190。虽然所有三个癌基因转化髓样（32 D cl3）和淋巴（Ba/F3）白细胞介素（IL）-3依赖性细胞系成为独立的IL-3的生存和生长，他们的能力，刺激增殖的Ba/F3淋巴细胞不同，直接与酪氨酸激酶活性。在小鼠骨髓转导/移植模型中，当使用5-氟尿嘧啶（5-FU）处理的供体时，三种形式的BCR/ABL在受体小鼠中诱导慢性粒细胞白血病（CML）样骨髓增殖综合征方面具有同等效力。前病毒整合的分析显示CML样疾病是多克隆的，并涉及多个髓系和B淋巴系，暗示了一个原始的多能靶细胞。二次移植显示，只有某些次要的克隆产生了第12天的脾集落和诱导的疾病，在第二次受体，这表明靶细胞群体之间的异质性。相反，当使用来自非5-FU治疗供体的骨髓时，在受体中观察到CML样疾病、B淋巴急性白血病和巨噬细胞肿瘤的混合物。P190 BCR/ABL诱发淋巴细胞白血病的潜伏期比P210或P230短。淋巴样白血病和巨噬细胞肿瘤的前病毒整合模式是寡聚或单克隆的，仅限于肿瘤细胞，这表明除了BCR/ABL转导外，还需要额外的事件才能完全恶性转化。这些结果并不支持P230 BCR/ABL在人类中诱导一种独特且侵袭性较低的CML形式的假设，并表明P190 BCR/ABL在人类CML中的罕见性可能反映了干细胞中Ph染色体发生期间BCR内含子1断裂点的罕见性，而不是P190和P210之间髓系白血病发生的内在差异。
The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3–dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)–like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)–treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non– 5-FU–treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.