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

Hes 1高水平表达常见于BCR-ABL阳性慢性粒细胞白血病急变期（CML-BC）。在小鼠骨髓移植（BMT）模型中，BCR-ABL和Hes 1的共表达诱导CML-BC样疾病;然而，潜在的机制仍不清楚。在这里，基于基因表达分析，我们表明，MMP-9的上调Hes 1在共同的髓系祖细胞（CMP）。启动子活性分析表明，Hes 1通过激活NF-κ B上调MMP-9。对20例CML-BC患者的分析显示，MMP-9在3例中高度表达，其中2例表现出高水平的Hes 1表达。有趣的是，MMP-9缺乏损害了与基质细胞层结合的表达BCR-ABL和Hes 1的CMP的鹅卵石区域形成能力。此外，这些CMP分泌MMP-9，促进可溶性Kit-配体（sKitL）从基质细胞释放，从而增强白血病细胞的增殖。与此一致，移植了表达BCR-ABL和Hes 1的CMP的小鼠在血清中表现出高水平的sKitL以及MMP-9。重要的是，MMP-9缺乏损害小鼠BMT模型中BCR-ABL和Hes 1诱导的CML-BC样疾病的发展。因此，Hes 1促进CML-BC的发展，部分通过MMP-9在白血病细胞中的上调。

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.