Page 82 - Haematologica July

Haematologica 2018 Volume 103(7):1160-1168
*CHSL and YZ contributed equally to this work.
Ferrata Storti Foundation
Myeloproliferative Disorders
JAK2V617F-bearing vascular niche enhances malignant hematopoietic regeneration following radiation injury
Chi Hua Sarah Lin,1* Yu Zhang,2* Kenneth Kaushansky3 and Huichun Zhan1,4
1Department of Medicine, Stony Brook School of Medicine, NY, USA; 2Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China; 3Office of the Sr. Vice President, Health Sciences, Stony Brook School of Medicine, NY, USA and 4Northport VA Medical Center, Northport, NY, USA
ABSTRACT
Myeloproliferative neoplasms are clonal stem cell disorders char- acterized by hematopoietic stem/progenitor cell expansion. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Abnormalities of the marrow microenvironment are beginning to be recognized as an important factor in the development of myeloproliferative neoplasms. Endothelial cells are an essential compo- nent of the hematopoietic vascular niche. Endothelial cells carrying the JAK2V617F mutation can be detected in patients with myeloprolifera- tive neoplasms, suggesting that the mutant vascular niche is involved in the pathogenesis of these disorders. Here, using a transgenic mouse expressing JAK2V617F specifically in all hematopoietic cells (including hematopoietic stem/progenitor cells) and endothelial cells, we show that the JAK2V617F-mutant hematopoietic stem/progenitor cells are relative- ly protected by the JAK2V617F-bearing vascular niche from an other- wise lethal dose of irradiation during conditioning for stem cell trans- plantation. Gene expression analysis revealed that chemokine (C-X-C motif) ligand 12, epidermal growth factor, and pleiotrophin are up-regu- lated in irradiated JAK2V617F-bearing endothelial cells compared to wild-type cells. Our findings suggest that the mutant vascular niche may contribute to the high incidence of disease relapse in patients with myeloproliferative neoplasms following allogeneic stem cell transplanta- tion, the only curative treatment for these disorders.
Introduction
The chronic Philadelphia chromosome (Ph1) negative myeloproliferative neo- plasms (MPNs) are clonal stem cell disorders characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in MPNs. However, the mechanisms responsible for the malignant HSPC expansion in MPNs are not fully understood, limiting the effectiveness of current treatment. Although the eti- ology of dysregulated hematopoiesis has been mainly attributed to the molecular alterations within the HSPC compartment, abnormalities of the marrow microen- vironment are beginning to be recognized as an important factor in the develop- ment of MPNs.1-5 The diseased niche could impair normal hematopoiesis and favor the competing malignant stem cells, which could contribute to the poor donor engraftment and high incidence of disease relapse following allogeneic stem cell transplantation (SCT), the only curative treatment for patients with MPNs.2,6-8
Endothelial cells (ECs) are an essential component of the hematopoietic niche and most HSPCs reside close to a marrow sinusoid (the “perivascular niche”).9 MPNs are characterized by increased marrow angiogenesis compared to normal marrow.10-12 Although the existence and cell of origin of endothelial progenitors is still a subject of debate, JAK2V617F mutation can be detected in endothelial pro- genitors derived from the hematopoietic lineage (the so-called endothelial cell
Correspondence:
huichun.zhan@stonybrookmedicine.edu or Huichun.Zhan@va.gov
Received: December 1, 2017. Accepted: March 14, 2018. Pre-published: March 22, 2018.
doi:10.3324/haematol.2017.185736
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1160
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1160
haematologica | 2018; 103(7)
ARTICLE