Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells

作者：Nakahara Fumio; Kitaura Jiro; Uchida Tomoyuki; Nishida Chiemi; Togami Katsuhiro; Inoue Daichi; Matsukawa Toshihiro; Kagiyama Yuki; Enomoto Yutaka; Kawabata Kimihito C; Lai Chen Yi; Komeno Yukiko; Izawa Kumi; Oki Toshihiko; Nagae Genta; Harada Yuka; Harada Hironori; Otsu Makoto; Aburatani Hiroyuki; Heissig Beate; Hattori Koichi; Kitamura Toshio^*

来源：Blood, 2014, 123(25): 3932-3942.

DOI：10.1182/blood-2013-01-476747

High levels of HES1 expression are frequently found in BCR-ABL(+) 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-kappa B. 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, CMPs expressing BCR-ABL and Hes1 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. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

• 出版日期2014-6-19
• 单位河北医科大学