Valosin-containing protein (VCP/p97) is prognostically unfavorable in pediatric AML, and negatively correlates with unfolded protein response proteins IRE1 and GRP78: A report from the Children's Oncology Group.
Document Type
Article
Publication Date
11-2023
Identifier
DOI: 10.1002/prca.202200109
Abstract
PURPOSE: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML).
EXPERIMENTAL DESIGN: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine (Ara-C), daunorubicin, and etoposide [ADE]) versus ADE plus bortezomib (ADE+BTZ).
RESULTS: Low-VCP expression was significantly associated with favorable 5-year overall survival (OS) rate compared to middle-high-VCP expression (81% versus 63%, p < 0.001), independent of additional bortezomib treatment. Multivariable Cox regression analysis identified VCP as independent predictor of clinical outcome. UPR proteins IRE1 and GRP78 had significant negative correlation with VCP. Five-year OS in patients characterized by low-VCP, moderately high-IRE1 and high-GRP78 improved after treatment with ADE+BTZ versus ADE (66% versus 88%, p = 0.026).
CONCLUSION AND CLINICAL RELEVANCE: Our findings suggest the potential of the protein VCP as biomarker in prognostication prediction in pediatric AML.
Journal Title
Proteomics Clin Appl
Volume
17
Issue
6
First Page
2200109
Last Page
2200109
MeSH Keywords
Child; Humans; Bortezomib; Cell Cycle Proteins; Endoplasmic Reticulum Chaperone BiP; Protein Serine-Threonine Kinases; Unfolded Protein Response; Valosin Containing Protein
Keywords
AML; ERAD; GRP78; IRE1; RPPA; UPR; VCP; leukemia; pediatric
Recommended Citation
Hoff FW, Qiu Y, Brown BD, et al. Valosin-containing protein (VCP/p97) is prognostically unfavorable in pediatric AML, and negatively correlates with unfolded protein response proteins IRE1 and GRP78: A report from the Children's Oncology Group. Proteomics Clin Appl. 2023;17(6):e2200109. doi:10.1002/prca.202200109
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Comments
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