FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells
FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells
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DOI：
10.1182/blood-2003-06-1969
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发表时间：
2004-01-01
期刊：
影响因子：
20.3
通讯作者：
Small, D
中科院分区：
文献类型：
--
作者：
Zheng, R;Levis, M;Small, D
Flt3受体酪氨酸激酶在大多数急性白血病中高表达，在急性髓系白血病(AML)中频繁突变。该受体的突变形式是结构性激活的，已知在AML中起重要作用，但目前尚不清楚过度表达的野生型(Wt)受体的激活状态。在这项研究中，我们检测了AML中野生型受体的激活状态。我们发现野生型受体在12个原发AML样本中的8个和13个白血病细胞系中的4个中被结构性地磷酸化/激活。为了解释为什么wtFlt3经常被激活，我们研究了这些细胞对其配体FL的表达。FL和Flt3的共同表达在原发AML样本和白血病来源的细胞系中都是普遍发现的。为了进一步证明自分泌信号是激活的原因，我们证明了条件培养液而不是新鲜培养液能够激活Flt3。此外，阻止配体与受体结合的抗体也会阻止Flt3的激活。最后，条件培养液中FL的耗尽能够阻断Flt3的激活。综上所述，这些发现提供了强有力的证据，表明wtFlt3在AML中经常被结构性激活，因此，像其突变形式一样，可能有助于白血病发生的信号改变。
The FLT3 receptor tyrosine kinase is highly expressed in most acute leukemias and frequently mutated in acute myeloid leukemia (AML). The mutated form of the receptor is constitutively activated and known to play an important role in AML, but the activation state of the overexpressed wild-type (wt) receptor is, at present, unknown. In this study, we examined the activation state of the wildtype receptor in AML. We found that the wild-type receptor was constitutively phosphorylated/activated in 8 of 12 primary AML samples and 4 of 13 leukemia cell lines. To explain why wtFLT3 is often activated, we investigated the expression of its ligand, FL, by these same cells. Coexpression of FL with FLT3 was a universal finding in both primary AML samples and leukemic-derived cell lines. To further prove that autocrine signaling was accounting for the activation, we showed that conditioned media but not fresh media was able to activate FLT3. In addition, an antibody that blocks binding of ligand to the receptor blocks FLT3 activation. Finally, depletion of FL from conditioned media is able to block the activation of FLT3. Taken together, these findings represent strong evidence that wtFLT3 is often constitutively activated in AML and thus, like its mutated form, might contribute to the altered signaling that characterizes leukemogenesis.