Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

Dijk, Anneke D. van; Bont, Eveline S.J.M. de; Kornblau, Steven M.

doi:10.1080/14789450.2020.1717951

Cited by 18 publications

(12 citation statements)

References 77 publications

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“…It is often upregulated as AML cells are dependent on the anti-apoptotic actions of MCL1 for maintenance of survival. Worth mentioning is that resistance against the BCL2-inhibitor venetoclax in AML is often caused by MCL1 overexpression [ 2 , 42 – 44 ].…”

Section: Discussionmentioning

confidence: 99%

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Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

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Background Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. Results Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. Conclusion This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

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Section: Discussionmentioning

confidence: 99%

“…The intensity of treatment is further guided by cytogenetic and somatic genetic risk stratifications. Yet, these classifications lack precise outcome prediction capability leaving patients survival variable [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

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“…Moreover, if parallel signaling pathways are activated in the tumor, the patient will show resistance to the administered targeted therapy. An emerging consensus view has therefore identified the need to include proteomic analyses in drug development pipelines and molecular screening programs [7][8][9][10][11] . However, successful implementation of this requires robust, reproducible, and affordable high-throughput proteomics technologies.…”

Section: Background and Summarymentioning

confidence: 99%

“…To date, RPPA technology has been, and is currently being, applied in several cancer clinical trials 11,36 , mostly retrospectively to detect markers of response and resistance [37][38][39][40][41][42][43][44][45] , but in some cases also prospectively to select the most appropriate therapy for a given patient 46,47 . As RPPA technology is readying itself for further implementation in drug development and clinical laboratory settings, there was a demand to evaluate the robustness and reproducibility of RPPA datasets derived from different RPPA platforms.…”

Section: Background and Summarymentioning

confidence: 99%

Multicenter reverse-phase protein array data integration

Koning

Bernhardt

Macleod

et al. 2021

Preprint

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Among the technologies available for protein biomarker discovery and validation, reverse-phase protein array (RPPA) benefits from unequalled sample throughput. Panels of high-quality antibodies enable the quantification by RPPA of protein abundance and posttranslational modifications in biological specimens with high precision and sensitivity. Incorporation of RPPA technology into clinical and drug development pipelines requires robust assays that generate reproducible results across multiple laboratories. We implemented the first international multicenter pilot study to investigate RPPA workflow variability. We characterized the proteomic responses of a series of breast cancer cells to two cancer drugs. This analysis quantified 86,832 sample spots, representing 108 biological samples, arrayed at three independent RPPA platforms. This unique integrated set of data is publicly available as a resource to the proteomic and cancer research communities to catalyse further analysis and investigation. We anticipate that this dataset will form a reference for the comparison of RPPA workflows and reagents, which can be expanded in the future, and will aid the identification of platform-robust treatment-marker antigens in breast cancer cells.

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“…8 In recent decades, targeted therapy has emerged as a promising strategy for the clinical treatment of AML to deal with the chemotherapy resistance. 9…”

Section: Introductionmentioning

confidence: 99%

KDM4C contributes to cytarabine resistance in acute myeloid leukemia via regulating the miR-328-3p/CCND2 axis through MALAT1

Xue

Ren

et al. 2021

Therapeutic Advances in Chronic Disease

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Aims: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm, in which relapse due to drug resistance is the main cause for treatment failure and the disease progression. In this study, we aimed to investigate the molecular mechanism of KDM4C-dependent MALAT1/miR-328-3p/CCND2 axis in cytarabine (Ara-C) resistance in the context of AML. Methods: Bioinformatics analysis was performed to predict the targeting relationships among KDM4C, MALAT1, miR-328-3p, and CCND2 in AML, which were validated with chromatin immunoprecipitation and dual-luciferase reporter assay. Methylation-specific polymerase chain reaction was conducted to detect the methylation of MALAT1 promoter. After conducting gain- and loss-of-function assays, we investigated the effect of KDM4C on cell Ara-C resistance. A NOD/SCID mouse model was established to further investigate the roles of KDM4C/MALAT1/miR-328-3p/CCND2 in Ara-C resistant AML cells. Results: KDM4C expression was upregulated in AML. KDM4C upregulation promoted the demethylation in the promoter region of MALAT1 to increase its expression, MALAT1 targeted and inhibited miR-328-3p expression, enhancing the Ara-C resistance of HL-60/A. miR-328-3p targeted and suppressed the expression of CCND2 in HL-60/A to inhibit the Ara-C resistance. Mechanistically, KDM4C regulated miR-328-3p/CCND2 through MALAT1, resulting in Ara-C resistance in AML. Findings in an in vivo xenograft NOD/SCID mouse model further confirmed the contribution of KDM4C/MALAT1/miR-328-3p/CCND2 in the Ara-C resistant AML. Conclusion: Our study demonstrated that KDM4C may up-regulate MALAT1 expression, which decreases the expression of miR-328-3p. The downregulation of miR-328-3p increased the level of CCND2, which induced the Ara-C resistance in AML.

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Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

Cited by 18 publications

References 77 publications

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Multicenter reverse-phase protein array data integration

KDM4C contributes to cytarabine resistance in acute myeloid leukemia via regulating the miR-328-3p/CCND2 axis through MALAT1

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