Dataset Information

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

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 .

SUBMITTER: van Dijk AD

PROVIDER: S-EPMC9041833 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

van Dijk Anneke D AD Hoff Fieke W FW Qiu Yihua Y Gerbing Robert B RB Gamis Alan S AS Aplenc Richard R Kolb E Anders EA Alonzo Todd A TA Meshinchi Soheil S Jenkins Gaye N GN de Bont Eveline S J M ESJM Kornblau Steven M SM Horton Terzah M TM

Proteomics. Clinical applications 20211117 2

<h4>Purpose</h4>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 p ...[more]

PMID: 34719869

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Project description:Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human skeletal homeostasis and represent a new genetic cause of HBM.

Dataset Information

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

Purpose

Experimental design

Results

Conclusion and clinical relevance

Publications

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

Similar Datasets

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