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Blood. 2014 Jun 19;123(25):3932-42. doi: 10.1182/blood-2013-01-476747. Epub 2014 May 13.

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

Author information

1
Division of Cellular Therapy, Advanced Clinical Research Center.
2
Laboratory of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine.
3
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, and.
4
Division of Stem Cell Signaling, Center for Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
5
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;
6
International Radiation Information Center and.
7
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; and.
8
Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
9
Division of Cellular Therapy, Advanced Clinical Research Center, Division of Stem Cell Signaling, Center for Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;

Abstract

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-κB. 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.

PMID:
24825862
DOI:
10.1182/blood-2013-01-476747
[Indexed for MEDLINE]
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