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

Authors

Fieke W Hoff
Yihua Qiu
Brandon D Brown
Robert B Gerbing
Amanda R Leonti
Rhonda E Ries
Alan S Gamis
Richard Aplenc
Edward Anders Kolb
Todd A Alonzo
Soheil Meshinchi
Gaye N Jenkins
Terzah M Horton
Steven M Kornblau

Publication Date

11-1-2023

Journal

Proteomics - Clinical Applications

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.

Keywords

Child, Humans, Bortezomib, Cell Cycle Proteins, Endoplasmic Reticulum Chaperone BiP, Protein Serine-Threonine Kinases, Unfolded Protein Response, Valosin Containing Protein, VCP, IRE1, GRP78, UPR, ERAD, leukemia, AML, RPPA, pediatric

DOI

10.1002/prca.202200109

PMID

37287368

PMCID

PMC10700663

PubMedCentral® Posted Date

11-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes