Molecular mechanisms of blast crisis transition and maintenance of leukemic stem cells in chronic myelogenous leukemia

BCR-ABL阳性的慢性粒细胞白血病急变期(CML-BC)常有Hes1的高表达。在小鼠骨髓移植(BMT)模型中，bcr-abl和Hes1共表达可诱导CML-BC样病，但其机制尚不清楚。在这里，基于基因表达分析，我们发现在常见的髓系祖细胞(CMPS)中，基质金属蛋白酶-9被Hes1上调。启动子活性分析表明，Hes1通过激活NF-kB上调了基质金属蛋白酶-9的表达。对20例CML-BC患者标本的分析表明，3例CML-BC患者的MMP9高表达，2例Hes1高表达。有趣的是，基质金属蛋白酶-9缺乏削弱了表达BCR-ABL和Hes1的CMP与基质细胞层结合的鹅卵石区域形成能力。此外，这些CMPS还分泌基质金属蛋白酶-9，促进基质细胞释放可溶性Kit-L，从而促进白血病细胞的增殖。相应地，移植了表达bcr-abl和hes1的CMPS的小鼠显示出血清中sKitL和MMP-9的高水平。重要的是，MMP9缺乏可抑制BCR-ABL和Hes1诱导的小鼠骨髓移植模型中CML-BC样病的发生。因此，Hes1促进了CML-BC的发展，部分是通过上调白血病细胞中的MMP-9来实现的。

High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. Thus, Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.