RRC ID 65992
Author Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D, Matsukawa T, Kagiyama Y, Enomoto Y, Kawabata KC, Chen-Yi L, Komeno Y, Izawa K, Oki T, Nagae G, Harada Y, Harada H, Otsu M, Aburatani H, Heissig B, Hattori K, Kitamura T.
Title Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells.
Journal Blood
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.
Volume 123(25)
Pages 3932-42
Published 2014-6-19
DOI 10.1182/blood-2013-01-476747
PII S0006-4971(20)40081-3
PMID 24825862
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics* Basic Helix-Loop-Helix Transcription Factors / metabolism Blast Crisis / genetics* Blast Crisis / metabolism Bone Marrow Transplantation / methods Cell Movement / genetics Cell Proliferation Flow Cytometry Fusion Proteins, bcr-abl / genetics Fusion Proteins, bcr-abl / metabolism Gene Expression Regulation, Leukemic* Homeodomain Proteins / genetics* Homeodomain Proteins / metabolism Humans Kaplan-Meier Estimate Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics* Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology Matrix Metalloproteinase 9 / genetics* Matrix Metalloproteinase 9 / metabolism Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Models, Genetic NF-kappa B / metabolism Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Transcription Factor HES-1 Up-Regulation
IF 17.794
Human and Animal Cells 10T1/2(RCB0247)