Scherle P A, Dorshkind K, Witte O N
Department of Microbiology, University of California, Los Angeles 90024.
Proc Natl Acad Sci U S A. 1990 Mar;87(5):1908-12. doi: 10.1073/pnas.87.5.1908.
The early stages of hematopoiesis have been difficult to study due to problems in obtaining homogeneous populations of progenitor cells that retain both self-renewal and differentiative capacities. We have developed an in vitro system in which transformation of murine bone-marrow cells with the BCR/ABL oncogene, a gene associated with stem-cell leukemias, leads to the outgrowth of clonal lines that have an early lymphoid progenitor cell phenotype. The progenitor cells retain immunoglobulin heavy and light chain genes in a germ-line configuration. These cells give rise in vitro to pre-B cells that have diverse diversity-joining (D-J) region rearrangements, and on transfer to mice with severe combined immune deficiency, differentiate to surface IgM+, immunoglobulin-secreting B cells that respond to T-cell help and function in an antigen-specific fashion. Although their growth is stimulated by BCR/ABL, the progenitor cells depend for continued growth on a stromal cell-derived soluble factor distinct from the pre-B-cell growth factor, interleukin 7. These findings show that BCR/ABL can promote proliferation of an early hematopoietic progenitor cell without preventing its differentiation. This system provides a means of studying the complete B-cell developmental process from clonal progenitor cell to end-stage plasma cell.
由于难以获得兼具自我更新和分化能力的均一祖细胞群体，造血作用的早期阶段一直难以研究。我们开发了一种体外系统，其中用与干细胞白血病相关的基因BCR/ABL对小鼠骨髓细胞进行转化，可导致具有早期淋巴祖细胞表型的克隆系生长。这些祖细胞以种系构型保留免疫球蛋白重链和轻链基因。这些细胞在体外产生具有多样的多样性连接（D-J）区域重排的前B细胞，并且在转移到严重联合免疫缺陷小鼠后，分化为表面IgM+、分泌免疫球蛋白的B细胞，这些B细胞对T细胞辅助有反应并以抗原特异性方式发挥作用。尽管它们的生长受到BCR/ABL的刺激，但祖细胞的持续生长依赖于一种不同于前B细胞生长因子白细胞介素7的基质细胞衍生可溶性因子。这些发现表明，BCR/ABL可促进早期造血祖细胞的增殖而不阻止其分化。该系统提供了一种研究从克隆祖细胞到终末浆细胞的完整B细胞发育过程的方法。
