III Medizinische Klinik, Technische Universität München, Munich, Germany.
Cancer Res. 2011 Jul 1;71(13):4696-706. doi: 10.1158/0008-5472.CAN-10-4136. Epub 2011 May 5.
Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34(+) progenitors from patients with FLT3-ITD(+) or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD(+) and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD(+) and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD(+) but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD(+) AML. Further, we defined a specific interaction between FLT3-ITD(+) progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone.
针对急性髓系白血病（AML）中组成性激活的 FMS 样酪氨酸激酶 3（FLT3）[FLT3-ITD]与酪氨酸激酶抑制剂（TKI）的相互作用，导致外周血白血病细胞清除，但骨髓中未发生此现象，这表明骨髓龛对白血病干细胞具有保护作用。在这项研究中，我们研究了基质龛细胞对接受 TKI SU5614 或索拉非尼治疗的 FLT3-ITD 或野生型 FLT3（FLT3-WT）AML 患者 CD34+祖细胞的影响。两种 TKI 均能有效且特异性地抑制 FLT3，并增加两种 FLT3-ITD（+）和 FLT3-WT 样本中未分裂祖细胞的比例。SU5614 和索拉非尼的治疗还减少了成熟白血病祖细胞的数量，而与基质的接触则可防止这种细胞丢失。相比之下，来自 FLT3-ITD（+）和 FLT3-WT AML 的原始长期祖细胞均对 TKI 具有抗性。在 SU5614 存在的情况下，与龛细胞的进一步接触可显著扩增长期 FLT3-ITD（+）祖细胞，但不会扩增 FLT3-WT 祖细胞，但在索拉非尼存在的情况下则不会发生这种情况。因此，第一代抑制剂的 TKI 未能根除 FLT3-ITD（+）AML 中的早期白血病干细胞/祖细胞。此外，我们还定义了 FLT3-ITD（+）祖细胞与龛细胞之间的特定相互作用，该相互作用使白血病祖细胞在 TKI 存在的情况下得以维持。总而言之，我们的发现表明，分子疗法可能对白血病祖细胞产生意想不到的影响，这凸显了开发选择性消除恶性干细胞克隆的策略的必要性。
