School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia.
Blood. 2012 Nov 8;120(19):4049-57. doi: 10.1182/blood-2012-06-436675. Epub 2012 Sep 18.
High levels of expression of wild-type Flt3 characterize many hematopoietic proliferative diseases and neoplasms, providing a potential therapeutic target. Using the c-Cbl RING finger mutant mouse as a model of a myeloproliferative disease (MPD) driven by wild-type Flt3, in the present study, we show that treatment with the Flt3 kinase inhibitor AC220 blocks MPD development by targeting Flt3(+) multipotent progenitors (MPPs). We found that daily administration of AC220 caused a marked reduction in Flt3 expression, induction of quiescence, and a significant loss of MPPs within 4 days. Unexpectedly, a robust Flt3 ligand-associated proliferative recovery response soon followed, preventing further loss of MPPs. However, continued AC220 treatment limited MPP recovery and maintained reduced, steady-state levels of cycling MPPs that express low levels of Flt3. Therefore, a finely tuned balance between the opposing forces of AC220 and Flt3 ligand production was established; whereas the Flt3 ligand blunted the inhibitory effects of AC220, the disease was held in remission for as long as therapy was continued. The net effect is a potent therapy indicating that patients with c-Cbl mutations, or those with similarly enhanced Flt3 signaling, may respond well to AC220 even after the induction of high levels of Flt3 ligand.
野生型 Flt3 的高表达特征存在于许多造血增殖性疾病和肿瘤中，为潜在的治疗靶点提供了依据。本研究利用 c-Cbl RING 指突变小鼠作为野生型 Flt3 驱动的骨髓增殖性疾病（MPD）模型，结果表明，Flt3 激酶抑制剂 AC220 通过靶向 Flt3(+)多能祖细胞（MPP）可阻断 MPD 的发展。我们发现，AC220 的每日给药可导致 Flt3 表达明显降低、诱导静止以及在 4 天内显著损失 MPP。出乎意料的是，很快出现了强烈的 Flt3 配体相关增殖恢复反应，从而防止了 MPP 的进一步损失。然而，持续的 AC220 治疗限制了 MPP 的恢复，并维持了低水平 Flt3 表达的循环 MPP 的稳定水平。因此，在相反的 AC220 和 Flt3 配体产生的力量之间建立了一个精细的平衡；虽然 Flt3 配体削弱了 AC220 的抑制作用，但只要继续治疗，疾病就会处于缓解状态。其净效应是一种有效的治疗方法，表明 c-Cbl 突变的患者，或那些具有类似增强的 Flt3 信号的患者，即使在诱导高水平 Flt3 配体后，也可能对 AC220 反应良好。
