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Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins
Fieke W Hoff1, Ti'ara L Griffen2, Brandon D Brown3
1Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-9030, USA.
Abstract:
DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.
Insights
DNA damage response (DDR) protein expression is altered in leukemia, forming distinct clusters with shared prognostic implications across different leukemia types. These patterns vary by disease and patient age.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA damage response (DDR) pathways are crucial in cancer development and treatment outcomes.
- Leukemia subtypes, including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), and chronic lymphocytic leukemia (CLL), exhibit varied responses to therapy.
- Understanding DDR protein expression is vital for leukemia prognosis and therapeutic strategies.
Purpose of the Study:
- To investigate the protein expression levels of 16 DNA damage recognition and repair (DNADR) proteins in leukemia.
- To identify distinct protein expression clusters within AML, T-ALL, and CLL.
- To evaluate the prognostic significance of these clusters and individual protein differences across leukemia subtypes and age groups.
Main Methods:
- Reverse Phase Protein Array (RPPA) methodology was employed to quantify protein expression.
- Protein expression data from 1310 AML, 361 T-ALL, and 795 CLL cases were analyzed.
- Clustering analysis was performed to identify protein expression patterns and their correlation with clinical outcomes.
Main Results:
- Five distinct protein expression clusters were identified, with three differing from normal CD34+ cells.
- Protein expression varied significantly between leukemia types (14/16 proteins) and by age in T-ALL and AML.
- Specific clusters showed shared prognostic implications for survival and remission duration in T-ALL and AML, with one cluster (C5) demonstrating favorable outcomes.
Conclusions:
- DNA damage response and repair protein expression is dysregulated in leukemia, forming recurrent, shared clusters with prognostic value.
- Individual protein expression patterns are associated with specific leukemia types and patient age.
- These findings highlight the potential of DDR protein profiling for refining leukemia classification and guiding treatment decisions.
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