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Chromatin Profiles Are Prognostic of Clinical Response to Bortezomib-Containing Chemotherapy in Pediatric Acute Myeloid Leukemia: Results from the COG AAML1031 Trial.
- Source :
-
Cancers . Apr2024, Vol. 16 Issue 8, p1448. 20p. - Publication Year :
- 2024
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Abstract
- Simple Summary: Bortezomib-containing chemotherapy did not improve the clinical outcome in the AAML1031 study in terms of overall survival and event-free survival compared to standard chemotherapy. We characterized epigenetically distinct proteomic profiles in a large cohort of pediatric patients that participated in this study using the reverse-phase protein array. We observed in the patient group that received standard therapy that a higher expression of 16 histone-modulating enzymes (HMEs) was an independent variable that predicted higher relapse risk three years after a second induction therapy compared to those with a lower HME protein expression. Also, there was significantly improved overall survival for those with a high HME expression who were treated with the bortezomib-containing chemotherapy, compared to high-HME patients treated without bortezomib. We also demonstrated that patients with a higher expression of HME had more open chromatin surrounding promoter sides compared to those with lower HME protein levels using ATAC-seq. The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 16
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 176876864
- Full Text :
- https://doi.org/10.3390/cancers16081448