Division of Hematology, University of Colorado Medical Center, Aurora, CO, USA.
Division of Hematology, University of Colorado Medical Center, Aurora, CO, USA.
Leuk Res. 2019 May;80:1-10. doi: 10.1016/j.leukres.2019.02.011. Epub 2019 Feb 28.
Iron metabolism is altered in a variety of cancers; however, little is known about the role of iron metabolism in the biology and response to therapy of acute myeloid leukemia (AML). Here we show that SLC40A1, the gene encoding the iron exporter ferroportin (FPN), is variably expressed among primary AMLs and that low levels are associated with good prognosis and improved outcomes. In particular, core binding factor (CBF) AMLs, which are associated with good outcomes with chemotherapy, consistently have low level of SLC40A1 expression. AML cell lines that expressed relatively low levels of FPN endogenously, or were engineered via gene knockdown, had an increased sensitivity to chemotherapy relative to controls expressing high levels of FPN. Primary FPN AML bulk cells also had increased sensitivity to Ara-C treatment, iron treatment and the combination of Ara-C and iron relative to FPN cells. FPN leukemic stem cells (LSCs) had decreased viability following addition of iron alone and in combination with Ara-C treatment relative to FPN LSCs. Together these observations suggest a model where FPN mediated iron metabolism may play a role in chemosensitivity and outcome to therapy in AML.
铁代谢在各种癌症中发生改变；然而，铁代谢在急性髓系白血病（AML）的生物学和治疗反应中的作用知之甚少。在这里，我们表明，编码铁输出蛋白铁蛋白（FPN）的基因 SLC40A1 在原发性 AML 中表达存在差异，低水平与良好的预后和更好的结果相关。特别是与化疗相关的核心结合因子（CBF）AML，其表达水平始终较低。内源性表达相对较低水平 FPN 的 AML 细胞系，或通过基因敲低工程改造的细胞系，相对于表达高水平 FPN 的对照细胞，对化疗具有更高的敏感性。原发性 FPN AML 批量细胞相对于 FPN 细胞，在用 Ara-C 处理、铁处理和 Ara-C 和铁联合处理时，对 FPN 表达的 AML 批量细胞也具有更高的敏感性。与单独用铁或与 Ara-C 联合处理相比，FPN 白血病干细胞（LSCs）中的铁单独添加和联合添加都会降低其活力。这些观察结果表明，FPN 介导的铁代谢可能在 AML 的化疗敏感性和治疗结果中发挥作用。
