Internal tandem duplications of the FLT3 gene are present in leukemia stem cells
Internal tandem duplications of the FLT3 gene are present in leukemia stem cells
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DOI：
10.1182/blood-2004-05-1902
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发表时间：
2005-07-15
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：
Levis, M;Murphy, KM;Small, D
FLT 3基因的内部串联重复突变（FLT 3/ITD突变）是急性髓性白血病（AML）中最常见的分子异常，并与总体生存率差相关。虽然正常的FLT 3受体在早期造血祖细胞中表达，但尚未确定白血病干细胞中是否存在FLT 3突变。在这项研究中，我们将原代AML样本分选为干细胞富集的CD 34（+）/CD 38（-）组分，然后分析分选和未分选细胞的FLT 3突变体-野生型比例。在每种情况下，FLT 3突变体-野生型比例没有通过选择CD 34（+）/CD 38（-）细胞而改变，这意味着突变存在于白血病干细胞中。我们使用干细胞富集部分移植非肥胖糖尿病-严重联合免疫缺陷（NOD-SCID）小鼠，然后证实FLT 3/ITD突变存在于所得的移植骨髓中。作为FLT 3/ITD信号传导在该移植模型中的重要性的最终测试，我们使用小分子FLT 3抑制剂CEP-701来抑制FLT 3/ITD干细胞的移植。综上所述，这些实验确定了FLT 3/ITD突变存在于白血病干细胞中，并且FLT 3抑制剂可能对这些细胞具有活性。
Internal tandem duplication mutations of the FLT3 gene (FLT3/ITD mutations) are the most frequent molecular abnormality in acute myeloid leukemia (AML) and are associated with a poor overall survival. While the normal FLT3 receptor is expressed in early hematopoietic progenitor cells, it has not been determined whether FLT3 mutations are present in the leukemic stem cells. In this study, we sorted primary AML samples into stem cell-enriched CD34(+)/CD38(-) fractions and then analyzed the sorted and unsorted cells for the FLT3 mutant-wild-type ratio. In each case, the FLT3 mutant-wild-type ratio was not changed by selection of CD34(+)/CD38(-) cells, implying that the mutations are present in the leukemic stem cells. We used the stem cell-enriched fraction to engraft nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice and then confirmed that the FLT3/ITD mutation was present in the resultant engrafted marrow. As a final test of the importance of FLT3/ITD signaling in this engraftment model, we used a small molecule FLT3 inhibitor, CEP-701, to inhibit engraftment of FLT3/ITD stem cells. Taken together, these experiments establish that the FLT3/ITD mutations are present in leukemia stem cells, and that FLT3 inhibitors may have activity against these cells.