Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells.
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.
Division of Cellular Therapy, Advanced Clinical Research Center.
Fumio
F
Nakahara
Division of Cellular Therapy, Advanced Clinical Research Center.
Jiro
J
Kitaura
Division of Cellular Therapy, Advanced Clinical Research Center.
Tomoyuki
T
Uchida
Laboratory of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine.
Chiemi
C
Nishida
Division of Cellular Therapy, Advanced Clinical Research Center.
Katsuhiro
K
Togami
Division of Cellular Therapy, Advanced Clinical Research Center.
Daichi
D
Inoue
Division of Cellular Therapy, Advanced Clinical Research Center.
Toshihiro
T
Matsukawa
Division of Cellular Therapy, Advanced Clinical Research Center.
Yuki
Y
Kagiyama
Division of Cellular Therapy, Advanced Clinical Research Center.
Yutaka
Y
Enomoto
Division of Cellular Therapy, Advanced Clinical Research Center.
Kimihito C
KC
Kawabata
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, and.
Lai
L
Chen-Yi
Division of Cellular Therapy, Advanced Clinical Research Center.
Yukiko
Y
Komeno
Division of Cellular Therapy, Advanced Clinical Research Center.
Kumi
K
Izawa
Division of Stem Cell Signaling, Center for Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
Toshihiko
T
Oki
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;
Genta
G
Nagae
International Radiation Information Center and.
Yuka
Y
Harada
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; and.
Hironori
H
Harada
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, and.
Makoto
M
Otsu
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;
Hiroyuki
H
Aburatani
Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Beate
B
Heissig
Laboratory of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine.
Koichi
K
Hattori
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;
Toshio
T
Kitamura
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D016044:Fusion Proteins, bcr-abl; D018398:Homeodomain Proteins; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human