The angiogenesis inhibitor vasostatin is regulated by neutrophil elastase-dependent cleavage of calreticulin in AML patients

Mans, Sarah; Banz, Yara; Mueller, Beatrice U; Pabst, Thomas (2012). The angiogenesis inhibitor vasostatin is regulated by neutrophil elastase-dependent cleavage of calreticulin in AML patients. Blood, 120(13), pp. 2690-9. Washington, D.C.: American Society of Hematology 10.1182/blood-2012-02-412759

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The calcium-binding protein calreticulin (CRT) regulates protein folding in the endoplasmic reticulum (ER) and is induced in acute myeloid leukemia (AML) cells with activation of the unfolded protein response. Intracellular CRT translocation to the cell surface induces immunogenic cell death, suggesting a role in tumor suppression. In this study, we investigated CRT regulation in the serum of patients with AML. We found that CRT is not only exposed by exocytosis on the outer cell membrane after treatment with anthracyclin but also ultimately released to the serum in vitro and in AML patients during induction therapy. Leukemic cells of 113 AML patients showed increased levels of cell-surface CRT (P < .0001) and N-terminus serum CRT (P < .0001) compared with normal myeloid cells. Neutrophil elastase was identified to cleave an N-terminus CRT peptide, which was characterized as vasostatin and blocked ATRA-triggered differentiation. Levels of serum vasostatin in patients with AML inversely correlated with bone marrow vascularization, suggesting a role in antiangiogenesis. Finally, patients with increased vasostatin levels had longer relapse-free survival (P = .04) and specifically benefited from autologous transplantation (P = .006). Our data indicate that vasostatin is released from cell-surface CRT and impairs differentiation of myeloid cells and vascularization of the bone marrow microenvironment.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Banz Wälti, Yara and Pabst, Thomas

ISSN:

0006-4971

Publisher:

American Society of Hematology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:32

Last Modified:

06 Dec 2013 13:34

Publisher DOI:

10.1182/blood-2012-02-412759

PubMed ID:

22915645

Web of Science ID:

000311615800023

URI:

https://boris.unibe.ch/id/eprint/12477 (FactScience: 218826)

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