Page 147 - Haematologica March 2020

Myeloproliferative Neoplasm
Multilevel defects in the hematopoietic niche in essential thrombocythemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):661-673
Ting Sun,1,3 Mankai Ju,1,3 Xinyue Dai,1 Huan Dong,1 Wenjing Gu,1 Yuchen Gao,1 Rongfeng Fu,1,3,4,5 Xiaofan Liu,1,3,4,5 Yueting Huang,1,3,4,5 Wei Liu,1,3,4,5 Ying Ch,1,3,4,5
Wentian Wang,1,3,4,5 Huiyuan Li,1,3,4,5 Yuan Zhou,1,4,7 Lihong Shi,1,4,6,7 Renchi Yang,1,2,3,4,5,6 and Lei Zhang1,2,3,4,5,6,7
1State Key Laboratory of Experimental Hematology; 2National Clinical Research Center for Blood Diseases; 3Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin; 4Tianjin Laboratory of Blood Disease Gene Therapy; 5CAMS Key Laboratory of Gene Therapy for Blood Diseases; 6CAMS Center for Stem Cell Medicine and 7PUMC Department of Stem Cell and Regenerative Medicine, Tianjin, China
ABSTRACT
The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, includ- ing functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced prolifera- tion, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosup- pressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased pro- liferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK–GSK3β–CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.
Introduction
In ET with the acquired JAK2V617F mutation, neoplastic clones take over the BM niche, and consequently normal hematopoiesis fails.1 Multiple mechanisms may be involved in this process; however, the specific mechanisms leading to the replacement of normal hematopoietic stem/progenitor cells (HSPC) by mutant HSPC remain unclear.
Hematopoiesis is a parenchymal process that takes place in the BM, wherein it is tightly regulated by a complex communication network involving various factors that collectively form the niche for hematopoiesis. All blood cells are derived from HSPC that are primarily present in the perivascular niche, along with mesenchymal stromal cells (MSC) that synthesize various factors promoting HSPC maintenance and/or quiescence.2,3 Perivascular stromal cells marked by nestin (NES) in the BM are closely associated with HSPC and can regulate the proliferation, differentiation, and long-term hematopoietic capacity of HSPC via direct or indirect pathways. Importantly, these NES-positive cells maintain HSPC in the BM, and when ectopi-
Correspondence:
LEI ZHANG
zhanglei1@ihcams.ac.cn
RENCHI YANG
rcyang@ihcams.ac.cn
LIHONG SHI
shilihongxys@ihcams.ac.cn
Received: December 5, 2019. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2018.213686
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/661
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