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Plasma Cell Disorders
TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1401-1413
Jumpei Teramachi,1,2 Hirofumi Tenshin,2,3 Masahiro Hiasa,2,3 Asuka Oda,2 Ariunzaya Bat-Erdene,2,4 Takeshi Harada,2 Shingen Nakamura,2
Mohannad Ashtar,2,3 So Shimizu,2,3 Masami Iwasa,2 Kimiko Sogabe,2 Masahiro Oura,2 Shiro Fujii,2 Kumiko Kagawa,2 Hirokazu Miki,5 Itsuro Endo,6 Tatsuji Haneji,1 Toshio Matsumoto7 and Masahiro Abe2
1Department of Histology and Oral Histology, Tokushima University Graduate School, Tokushima, Japan; 2Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan; 3Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan; 4Department of Immunology and Laboratory Medicines, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia; 5Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan; 6Department of Chronomedicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan and 7Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan
ABSTRACT
Along with tumor progression, the bone marrow microenviron- ment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-b-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 in order to decrease the expression of criti- cal mediators for MM growth and survival, including PIM2, MYC, Mcl- 1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSC) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-B ligand (RANKL) expression by BMSC. TAK1 inhibition effectively impaired MM cell adhesion to BMSC to disrupt the support of MM cell growth and survival by BMSC. Furthermore, TAK1 inhibition suppressed osteo- clastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.
Introduction
Multiple myeloma (MM) has a unique propensity to almost exclusively develop in the bone marrow and generate devastating bone destruction. MM cells enhance osteoclast (OC) formation and activity, and suppress osteoblastic differentiation from bone marrow stromal cells (BMSC), leading to extensive bone destruction with rapid development of osteolytic lesions.1,2 Angiogenesis is also enhanced through these cellular interactions.3,4 The types of cells surrounding MM cells cre- ate a cellular microenvironment suitable for MM cell growth and survival to con- fer drug resistance, which can be termed the “MM niche”.
Correspondence:
JUMPEI TERAMACHI
jumptera@okayama-u.ac.jp
MASAHIRO ABE
masabe@tokushima-u.ac.jp
Received: August 7, 2019. Accepted: April 2, 2020. Pre-published: April 9, 2020.
https://doi.org/10.3324/haematol.2019.234476
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