Jaiswal Siddhartha, Traver David, Miyamoto Toshihiro, Akashi Koichi, Lagasse Eric, Weissman Irving L
Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10002-7. doi: 10.1073/pnas.1633833100. Epub 2003 Jul 30.
Chronic myelogenous leukemia is a myeloproliferative disorder (MPD) that, over time, progresses to acute leukemia. Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny. Chronic myelogenous leukemia is therefore classified as an HSC disorder in which a clone of multipotent HSCs is likely to be malignantly transformed, although direct evidence for malignant t(9;22)+ HSCs is lacking. To test whether HSC malignancy is required, we generated hMRP8p210BCR/ABL transgenic mice in which expression of BCR/ABL is absent in HSCs and targeted exclusively to myeloid progenitors and their myelomonocytic progeny. Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis. To address whether additional oncogenic events are required for progression to acute disease, we crossed hMRP8p210BCR/ABL mice to apoptosis-resistant hMRP8BCL-2 mice. Of 18 double-transgenic animals, 9 developed acute myeloid leukemias that were transplantable to wild-type recipients. Taken together, these data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.
慢性粒细胞白血病是一种骨髓增殖性疾病（MPD），随着时间的推移会进展为急性白血病。这两个过程都与t(9;22)染色体易位密切相关，该易位在造血干细胞（HSCs）及其后代中产生BCR/ABL融合基因。因此，慢性粒细胞白血病被归类为一种HSC疾病，其中多能HSCs的一个克隆可能发生恶性转化，尽管缺乏恶性t(9;22)+ HSCs的直接证据。为了测试是否需要HSC恶性肿瘤，我们生成了hMRP8p210BCR/ABL转基因小鼠，其中BCR/ABL在HSCs中不表达，仅靶向髓系祖细胞及其髓单核细胞后代。13只BCR/ABL转基因创始人小鼠中有4只发展为慢性MPD，但只有1只进展为急变期。为了解决进展为急性疾病是否需要额外的致癌事件，我们将hMRP8p210BCR/ABL小鼠与抗凋亡的hMRP8BCL-2小鼠杂交。在18只双转基因动物中，9只发展为可移植到野生型受体的急性髓系白血病。综上所述，这些数据表明，在HSCs中不表达BCR/ABL的小鼠中可能出现MPD，并且抑制程序性细胞死亡的额外突变可能在这种疾病向急变期白血病的转变中起关键作用。
