1. Academic Validation
  2. Multilevel defects in the hematopoietic niche in essential thrombocythemia

Multilevel defects in the hematopoietic niche in essential thrombocythemia

  • Haematologica. 2020 Mar;105(3):661-673. doi: 10.3324/haematol.2018.213686.
Ting Sun 1 2 Mankai Ju 1 2 Xinyue Dai 1 Huan Dong 1 Wenjing Gu 1 Yuchen Gao 1 Rongfeng Fu 1 2 3 4 Xiaofan Liu 1 2 3 4 Yueting Huang 1 2 3 4 Wei Liu 1 2 3 4 Ying Ch 1 2 3 4 Wentian Wang 1 2 3 4 Huiyuan Li 1 2 3 4 Yuan Zhou 1 3 5 Lihong Shi 6 3 7 5 Renchi Yang 8 9 2 3 4 7 Lei Zhang 10 9 2 3 4 7 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology.
  • 2 Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.
  • 3 Tianjin Laboratory of Blood Disease Gene Therapy.
  • 4 CAMS Key Laboratory of Gene Therapy for Blood Diseases.
  • 5 PUMC Department of Stem Cell and Regenerative Medicine, Tianjin, China.
  • 6 State Key Laboratory of Experimental Hematology shilihongxys@ihcams.ac.cn.
  • 7 CAMS Center for Stem Cell Medicine.
  • 8 State Key Laboratory of Experimental Hematology rcyang@ihcams.ac.cn.
  • 9 National Clinical Research Center for Blood Diseases.
  • 10 State Key Laboratory of Experimental Hematology zhanglei1@ihcams.ac.cn.
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, including 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 proliferation, 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 immunosuppressive 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 proliferation, 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.

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