DEFECTIVE GLYCOLYSIS IN BONE MARROW ENDOTHELIAL CELLS OF PATIENTS WITH POOR GRAFT FUNCTION POST-ALLOTRANSPLANT IDENTIFIES A POTENTIAL THERAPEUTIC STRATEGY
Author(s): ,
Zhong-Shi Lyu
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China;Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China
,
Wei-Li Yao
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Qi Wen
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Fei-Fei Tang
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Min-Min Shi
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China;Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China
,
Hong-Yan Zhao
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Yu Wang
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Lan-Ping Xu
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Xiao-Hui Zhang
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
,
Hsiang-Ying Lee
Affiliations:
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China;School of Life Sciences,Peking University,Beijing,China
,
Xiao-Jun Huang
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China;Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China
Yuan Kong
Affiliations:
Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of HSCT,Peking University,Beijing,China
EHA Library. Lyu Z. Jun 15, 2019; 267477; S894
Zhong-Shi Lyu
Zhong-Shi Lyu
Contributions
×
Abstract

Abstract: S894

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:00 - 17:15

Location: Hall 3A

Background
Poor graft function (PGF), defined as pancytopenia, is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Its pathobiology, found by our previous studies (BBMT 2013; BMT 2016; Blood 2016), involves the dysfunctional and reduced bone marrow(BM) endothelial cells(ECs), which is a key component of BM microenvironment to modulate the physiology and regeneration of hematopoietic stem cells (HSCs). Furthermore, the aberrant BM ECs derived from PGF patients could be attenuated by ROS scavenger, N-acetyl-L-cysteine (NAC), in vitro (Blood 2016), implying the pivotal role of ROS in the impaired BM ECs of PGF patients. However, the mechanisms underlying the abnormal BM ECs of PGF, remains to be elucidated. Energy metabolism plays an instrumental role in maintaining EC function, and markedly perturbed of EC metabolism, results in high level of ROS and dysfunction of ECs, and contributes to many pathologies, like cancer and diabetes. However, little is known about the metabolism state and its role in BM ECs of PGF patients post-allotransplant.

Aims
To determine the metabolic state and its role in BM ECs of PGF patients post-allotransplant. Moreover, to evaluate the therapeutical potential of anti-metabolic drugs to the dysfunctional BM ECs derived from PGF patients. 

Methods
This prospective case-control study enrolled 15 patients with PGF, 30 matched patients with good graft function (GGF), defined as persistent successful engraftment after allotransplant, and 15 healthy donors (HD). The mitochondrial mass, membrane potential and the protein expression level of metabolism enzymes, CPT1A and PFKFB3 in BM ECs, were detected by flow cytometry. In addition, the cultivated BM ECs were derived from BM mononuclear cells (BMMNCs), as previous reported. The glycolysis inhibitor 3-PO was administrated to the 5-day cultivated BM ECs until testing on day 7. The functions of BM ECs were evaluated by apoptosis, migration and tube formation assays. Glucose metabolism levels were measured by glucose consumption and lactate production assays.

Results
In this study, elevated expression of the glycolytic activator PFKFB3 was observed in BM ECs of PGF patients, when compared with those of GGF patients and HD, but not the lipid metabolism enzyme CPT1A, mitochondrial mass or membrane potential. Moreover, glycolysis (PFKFB3) inhibitor 3-PO treatment quantitatively and functionally improved BM ECs derived from patients with PGF in vitro. Mechanistically, we demonstrated that the aberrant glycolysis in BM ECs of PGF could be reduced by NAC treatment in vitro, while the glycolysis in BM ECs of GGF could be induced by hydrogen peroxide treatment in vitro, consistent with ROS-induced dysfunction of BM ECs. Furthermore, Glycolysis inhibitor 3-PO treatment attenuated the perturbed function and number of BM ECs derived from GGF patients treated with hydrogen peroxide.

Conclusion
These findings reveal that hyper-glycolysis is involved in the pathobiology of BM ECs of PGF patients, which is triggered by their high level of ROS. In turn, this metabolism alteration, mediated ROS-induced dysfunction of BM ECs. What’s more, the impaired BM ECs of PGF could be attenuated by glycolysis inhibitor 3-PO in vitro. Given that several glycolysis enzyme PFKFB3 inhibitors entered Phase I clinical trials in patients with advanced solid malignancies. Our findings might merit further consideration of targeting BM ECs glycolysis as a promising therapeutic approach for PGF patients post-allotransplant in the future. 

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Allogeneic hematopoietic stem cell transplant, Endothelial cell, Endothelial dysfunction, Hematopoietic microenvironment

By continuing to browse or by clicking “Accept Terms & all Cookies”, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies