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Hematopoiesis
Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression
Xiaoyan Liu, Yanping Ma, Rongrong Li, Dan Guo, Nan Wang, Yangyang Zhao, Jing Yin, Qian Ren, Yongmin Lin and Xiaotong Ma
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
ABSTRACT
The bone marrow microenvironment regulates normal and malig- nant hematopoiesis, but the underlying molecular mechanisms remain poorly defined. Using a chimeric mice model, we demon- strate that Twist1 deletion in the bone marrow microenvironment results in alteration of multiple niche cells as well as downregulated expression of major hematopoietic stem cell supportive factors. The perturbed microenvironment reduces hematopoietic stem cell homing and reten- tion, impairs hematopoietic stem cell self-renewal and induces myeloid skewing. Nevertheless, it accelerates the progression of MLL-AF9 leukemia, which is partially mediated by Jagged-2-dependent Notch sig- naling. Our data provide the first demonstration of a pivotal role of TWIST1 in favoring normal hematopoiesis and hampering leukemia development. They also bring new insights into the role of the bone marrow niche in driving the development of acute myeloid leukemia, and suggest possible new avenues, exploiting the niche, to improve leukemia treatments.
Introduction
Hematopoietic stem cells (HSC) reside in a special bone marrow (BM) niche, which regulates their localization, self-renewal and differentiation. Studies have identified several major cell types of the niche, including mesenchymal stem cells (MSC), osteolineage cells (OLC), adipocytes and vascular endothelial cells (EC).1-5 Besides the key cellular components, some growth and survival factors are also indispensable components of the niche, including C-X-C motif chemokine 12 ligand (CXCL12), vascular cell adhesion molecule1 (VCAM1),6,7 stem cell factor (SCF)4 and osteopontin.8 A sophisticated network of interactions between these multiple BM cells, extracellular factors and adhesion molecules is essential to regulate different HSC properties during homeostasis and keep normal hematopoiesis in check.
Acute myeloid leukemia (AML) has been considered for decades to be a disorder intrinsic to hematopoietic cells; however, evidence is accumulating that the microenvironment exerts more than a mere bystander effect. Leukemic cells can remodel the niche into a permissive environment favoring leukemic stem cell (LSC) expansion over normal HSC maintenance.9 Recently, emerging evidence even points to a role for the BM niche as a driver of disease maintenance/progression. Krause et al. showed that osteoblast-specific activation of the parathyroid hormone receptor enhances MLL-AF9 oncogene-induced AML in mouse transplantation models.10 To date, there are still few studies concerning the role of the bone marrow niche in ini- tiating and maintaining AML and relevant mechanisms remain elusive.
TWIST1 is a highly conserved transcription factor belonging to the basic helix- loop-helix family and is implicated in diverse developmental systems.11-13 Studies have revealed that TWIST1 is a key regulator of MSC self-renewal, enhances their life-span, inhibits MSC osteo/chondrogenic differentiation and promotes adi- pogenic differentiation.14-16 Twist1 haploisufficiency leads to Saethre-Chotzen syn- drome, which is characterized by alterations in osteogenic precursor cell prolifera- tion, differentiation and survival.17 Recent studies have demonstrated that TWIST1 promotes angiogenesis by inducing EC proliferation and migration, and deregula- tion of this mechanism mediates pathological angiogenesis.18,19 Arthur et al. showed
Ferrata Storti Foundation
Haematologica 2018 Volume 103(12):1969-1979
Correspondence:
maxt@ihcams.ac.cn
Received: February 8, 2018. Accepted: July 17, 2018. Pre-published: July 19, 2018.
doi:10.3324/haematol.2018.190652
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/1969
©2018 Ferrata Storti Foundation
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