Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA

Anneke D van Dijk; Fieke W Hoff; Yihua Qiu; Robert B Gerbing; Alan S Gamis; Richard Aplenc; E Anders Kolb; Todd A Alonzo; Soheil Meshinchi; Gaye N Jenkins; Eveline S J M de Bont; Steven M Kornblau; Terzah M Horton

doi:10.1002/prca.202100072

Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA

Proteomics Clin Appl. 2022 Mar;16(2):e2100072. doi: 10.1002/prca.202100072. Epub 2021 Nov 17.

Authors

Affiliations

¹ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Divison of Pediatric Oncology/Hematology, Groningen, The Netherlands.
² Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
³ Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
⁴ COG Statistics and Data Center, Monrovia, California, USA.
⁵ Department of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
⁶ Division of Pediatric Oncology/Stem Cell Transplant, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁷ Nemours Center for Cancer and Blood Disorders, Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA.
⁸ Keck School of Medicine, University of Southern California, California, USA.
⁹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁰ Department of Pediatrics, Baylor College of Medicine/Dan L. Duncan Cancer Center and Texas Children's Cancer Center, Houston, Texas, USA.

Abstract

Purpose: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status.

Experimental design: RelA-total and phosphorylation at serine 536 (RelA-pSer⁵³⁶ ) were measured in 483 patient samples using reverse phase protein array technology.

Results: In ADEB-treated patients, low-RelA-pSer⁵³⁶ was favorably prognostic when compared to high-RelA-pSer⁵³⁶ (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer⁵³⁶ patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer⁵³⁶ and 295 other assayed proteins identified a strong correlation with HSF1-pSer³²⁶ , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer⁵³⁶ and low-HSF1-pSer³²⁶ was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013).

Conclusion and clinical relevance: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer⁵³⁶ and low-HSF1-pSer³²⁶ .

Keywords: B ortezomib; RPPA; leukemia; pediatric; proteomics.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Bortezomib / pharmacology
Bortezomib / therapeutic use
Child
Cytarabine / adverse effects
Humans
Leukemia, Myeloid, Acute* / drug therapy
NF-kappa B*
Neoplasm Recurrence, Local / chemically induced
Neoplasm Recurrence, Local / drug therapy
Phosphorylation
Transcription Factor RelA / therapeutic use

Substances

NF-kappa B
RELA protein, human
Transcription Factor RelA
Cytarabine
Bortezomib

Abstract

Publication types

MeSH terms

Substances

Grants and funding