Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
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慢性粒细胞白血病(CML)的复发是由具有类似于造血干细胞(HSCs)的重建能力的干细胞触发的，而CML干细胞是酪氨酸激酶抑制剂(TKIs)药物治疗的耐药来源之一。亲水性病毒整合位点1(EVI1)是HSC调控中的关键转录因子，已知可预测髓系恶性肿瘤的不良预后，然而，无法前瞻性分离EVI1高表达的白血病细胞阻碍了对个体内EVI1高表达细胞的功能评估。将CML导入Evi1-内部核糖体进入位点(IRES)-绿色荧光蛋白(GFP)敲入小鼠，这是一种多功能的HSC报告株，使我们能够从个体中分离出Evi1高CML细胞。慢性粒细胞白血病慢性期(CML-CP)的Evi1-IRES-GFP等位基因模型，通过BCR-ABL逆转录病毒过表达和与BCR-ABL转基因小鼠杂交，发现Evi1主要富含干细胞部分，与增强的增殖和白血病启动能力相关，Evi1高表达的CML-CP细胞对TKIs表现出抵抗。在Evi1-IRES-GFP敲入小鼠中过表达BCR-ABL和NUP98-HOXA9，建立了CML急变期模型(CML-BC)，其中Evi1高表达的CML-BC细胞成为主要群体，而不是CML-CP模型中的少数群体，表明Evi1高表达的CML-BC细胞具有更大的重复性疾病的潜力和对TKIs的耐药性。此外，考虑到Evi1杂合子改善了CML-CP和CML-BC的发展，并且Evi1和bcr-abl的结合导致了类似于CML-BC的急性髓系白血病，Evi1可以作为一个强有力的驱动因素来调节CML的发展。此外，在人类CML-CP病例中，我们发现EVI1在单细胞水平上在干细胞丰富的CD34+CD38-CD90+组分中高表达。这是第一个直接阐明Evi1高表达的白血病细胞本身具有优于Evi1低表达细胞的致癌自我更新潜能的报道，突出了Evi1作为CML干细胞的一个有价值的功能标记物的作用。
Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR–ABL and by crossing BCR–ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR–ABL and NUP98–HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR–ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38–CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.
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