FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.
FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.
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DOI：
10.3324/haematol.2022.282472
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发表时间：
2023-11-01
期刊：
影响因子：
10.1
通讯作者：
Kim, Hee-Je
中科院分区：
文献类型：
--
作者：
Lee, Ji Yoon;Lee, Sung-Eun;Han, A-Reum;Lee, Jongeun;Yoon, Young-sup;Kim, Hee-Je
治疗难治性急性髓细胞白血病（AML）患者仍然具有挑战性。目前对于难治性AML没有有效的治疗方法。越来越多的证据表明，难治性/复发性AML与白血病原始细胞相关，白血病原始细胞可赋予抗癌药物耐药性。我们以前曾报道过Fms相关酪氨酸激酶4（FLT 4）的高表达与AML中癌症活动增加相关。然而，FLT 4在白血病母细胞中的功能作用仍然未知。在此，我们探讨了FLT 4在难治性白血病患者的白血病原始细胞中表达的意义以及AML原始细胞存活的机制。AML母细胞中FLT 4的抑制或缺失抑制了免疫功能低下小鼠的骨髓归巢，并阻断了AML母细胞的植入。此外，FLT 4抑制MAZ 51，一种拮抗剂，有效地减少了白血病细胞衍生的集落形成单位的数量，并增加了来自难治性患者的原始细胞的凋亡时，它与阿糖胞苷下血管内皮生长因子C，其配体共同治疗。细胞溶质FLT 4高表达的AML患者通过内化机制与AML难治性状态相关。总之，FLT 4在白血病发生和难治性中具有生物学功能。这一新的见解将有助于AML的靶向治疗和预后分层。
Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.
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