STAT5 signaling is required for the efficient induction and maintenance of CML in mice
STAT5 signaling is required for the efficient induction and maintenance of CML in mice
复制标题
DOI：
10.1182/blood-2005-10-4110
复制
发表时间：
2006-06-15
期刊：
影响因子：
20.3
通讯作者：
Ilaria, Robert L., Jr.
中科院分区：
文献类型：
--
作者：
Ye, Dan;Wolff, Nicholas;Ilaria, Robert L., Jr.
信号转导子和转录激活子 5 (STAT5) 在慢性粒细胞白血病 (CIVIL) 中的作用存在争议。为了阐明 STAT5 信号在 P210(BCR/ABL) 白血病发生中的作用，将 P210 引入原代小鼠 STAT5A 缺陷型 (STAT5A(-/-)) 骨髓 (BM) 细胞中，与 STAT5A/5B 双敲除 BM 细胞不同，该细胞没有主要的内在造血缺陷。有趣的是，只有 21% 的用 P210 转导的 STAT5A(-/-) BM 细胞重建的小鼠出现了经典的 CIVIL，而 P210/STAT5A(+/+) 和 P210/STAT5A(+/-) 重建的动物的这一比例为 80% 至 100%。其余的 P210/STAT5A(-/-) 动物死于急性 B 细胞淋巴细胞白血病 (ALL) 样疾病 (32%) 或 CML/ALL 混合疾病 (47%)，反映了 CML 的诱导和维持受损，而 CML 通常在该小鼠模型中占主导地位。在最终发展为 CIVIL 的小鼠中，P210/STAT5A-/- 动物的存活时间延长，骨髓不成熟程度增加。重要的是，用共表达 P210 和显性失活 STAT5 的 BM 细胞重建野生型小鼠也显着降低了 CML 的发生率，且不损害 ALL 的诱导。总之，这些发现表明 STAT5 和 STAT5A 在小鼠 CML-Ilke 疾病的发病机制中发挥重要作用。对参与 CML 诱导的 STAT5 靶基因的更深入了解可能会产生影响 CML 祖细胞生物学的新治疗靶点。
The role of signal transducers and activators of transcription 5 (STAT5) in chronic myelogenous leukemia (CIVIL) is controversial. To clarify the role of STAT5 signaling in P210(BCR/ABL) leukemogenesis, P210 was introduced into primary murine STAT5A-deficient (STAT5A(-/-)) bone marrow (BM) cells, which, unlike STAT5A/5B double knockout BM cells, have no major intrinsic hematopoletic defects. Interestingly, only 21% of mice reconstituted with P210-transduced STAT5A(-/-) BM cells developed classic CIVIL, compared with 80% to 100% of P210/STAT5A(+/+) and P210/STAT5A(+/-)-reconstituted animals. The remainder of P210/STAT5A(-/-) animals died from an acute B-cell lymphoblastic leukemia (ALL)-like disease (32%) or a CML/ ALL mix (47%), reflecting impairment in the induction and maintenance of CML, which normally predominates in this mouse model. Of mice that ultimately developed CIVIL, P210/STAT5A-/- animals had prolonged survival and increased myeloid immaturity. Importantly, reconstitution of wild-type mice with BM cells coexpressing P210 and dominant-negative STAT5 also profoundly reduced the incidence of CML, without impairing the induction of ALL. Altogether, these findings indicate that STAT5 and STAT5A play an important role in the pathogenesis of the CML-Ilke disease in mice. A greater understanding of the STAT5 target genes involved in CML induction may lead to new therapeutic targets that influence CML progenitor cell biology.