CBL-B is required for leukemogenesis mediated by BCR-ABL through negative regulation of bone marrow homing
CBL-B is required for leukemogenesis mediated by BCR-ABL through negative regulation of bone marrow homing
复制标题
DOI：
10.1038/leu.2012.331
复制
发表时间：
2013-05-01
期刊：
影响因子：
11.4
通讯作者：
Barber, D. L.
中科院分区：
文献类型：
--
作者：
Badger-Brown, K. M.;Gillis, L. C.;Barber, D. L.
BCR-ABL通过多种信号底物的异常调节诱导慢性髓细胞白血病（CML）。先前的研究表明，BCR-ABL介导CBL-B蛋白水平的下调。进行小鼠骨髓移植（BMT）研究以评估Cbl-b对BCR-ABL诱导的疾病的贡献。Cbl-b（-/-）受体的主要表型是CML样骨髓增生性疾病（MPD），与野生型动物相似，但潜伏期较长，循环白细胞数量减少，脾脏重量减轻。尽管与野生型动物相比白血病负荷降低，但Cbl-b（-/-）动物显示Gr-1（+）/Mac-1（+）脾细胞和嗜中性粒细胞数量增加。基于先前CBL-B依赖性向SDF-1 α运动的证据，我们假设Cbl-b缺乏可能会损害移植过程中的骨髓定位。归巢实验显示Cbl-b（-/-）细胞向骨髓的迁移减少。BCR-ABL转导的Cbl-b（-/-）细胞的股内移植显示与野生型移植物相同的疾病发展潜伏期，支持Cbl-b缺陷减少白血病细胞向骨髓的归巢，并在CML发展过程中干扰表达BCR-ABL的恶性克隆的增殖的结论。
BCR-ABL induces chronic myeloid leukemia (CML) through the aberrant regulation of multiple signaling substrates. Previous research has shown that BCR-ABL mediates down-modulation of CBL-B protein levels. A murine bone marrow transplantation (BMT) study was performed to assess the contribution of Cbl-b to BCR-ABL-induced disease. The predominant phenotype in the Cbl-b(-/-) recipients was a CML-like myeloproliferative disease (MPD) similar to that observed in the wild-type animals, but with a longer latency, diminished circulating leukocyte numbers and reduced spleen weights. Despite the decreased leukemic burden in comparison to their wild-type counterparts, the Cbl-b(-/-) animals displayed enhanced numbers of Gr-1(+)/Mac-1(+) spleen cells and neutrophilia. On the basis of prior evidence of CBL-B-dependent motility toward SDF-1 alpha, we hypothesized that Cbl-b deficiency might impair bone marrow localization during transplantation. Homing experiments showed reduced migration of Cbl-b(-/-) cells to the bone marrow. Intrafemoral transplantation of BCR-ABL-transduced Cbl-b(-/-) cells revealed equivalent latency of disease development to the wild-type transplants, supporting the conclusion that Cbl-b deficiency diminishes homing of leukemic cells to the bone marrow, and perturbs the proliferation of BCR-ABL-expressing malignant clones during CML development.