Comprehensive Analysis of ECHDC3 As a Potential Biomarker and Therapeutic Target for Acute Myeloid Leukemia: Bioinformatic Analysis and Experimental Verification

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 Sep 29

PMID 36172164

Authors

Yijing Zhao

Li-Ting Niu

Li-Juan Hu

Meng Lv

Affiliations

Soon will be listed here.

Abstract

Background: Enoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34 progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.

Methods: In the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People's Hospital and tested for ECHDC3 in enriched CD34 cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.

Results: By Kaplan-Meier analysis, patients with ECHDC3 demonstrated inferior overall survival (OS) compared to those with ECHDC3 both in the training (2-year OS, 55.6% . 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% . 24.3%, p = 0.002). In addition, ECHDC3 predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% . 26.3%, p = 0.039) or FLT3+NPM1- adverse (adv) risk (4-year OS, 6.4% . 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013-1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% . 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.

Conclusion: These bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.

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References

Silbiger V, Luchessi A, Hirata R, Lima-Neto L, Cavichioli D, Carracedo A . Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome. Clin Chim Acta. 2013; 421:184-90. DOI: 10.1016/j.cca.2013.03.011. View

Lv M, Wang K, Huang X . Myeloid-derived suppressor cells in hematological malignancies: friends or foes. J Hematol Oncol. 2019; 12(1):105. PMC: 6805310. DOI: 10.1186/s13045-019-0797-3. View

Dohner H, Estey E, Amadori S, Appelbaum F, Buchner T, Burnett A . Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2009; 115(3):453-74. DOI: 10.1182/blood-2009-07-235358. View

Trabanelli S, Chevalier M, Martinez-Usatorre A, Gomez-Cadena A, Salome B, Lecciso M . Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis. Nat Commun. 2017; 8(1):593. PMC: 5605498. DOI: 10.1038/s41467-017-00678-2. View

Hu X, Wang B, Chen Q, Huang A, Fu W, Liu L . A clinical prediction model identifies a subgroup with inferior survival within intermediate risk acute myeloid leukemia. J Cancer. 2021; 12(16):4912-4923. PMC: 8247394. DOI: 10.7150/jca.57231. View

Sharma N, Chuang Key C, Civelek M, Wabitsch M, Comeau M, Langefeld C . Genetic Regulation of Enoyl-CoA Hydratase Domain-Containing 3 in Adipose Tissue Determines Insulin Sensitivity in African Americans and Europeans. Diabetes. 2019; 68(7):1508-1522. PMC: 6609988. DOI: 10.2337/db18-1229. View

Bloomfield C, Estey E, Pleyer L, Schuh A, Stein E, Tallman M . Time to repeal and replace response criteria for acute myeloid leukemia?. Blood Rev. 2018; 32(5):416-425. DOI: 10.1016/j.blre.2018.03.006. View

Stevens B, Jones C, Pollyea D, Culp-Hill R, DAlessandro A, Winters A . Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer. 2021; 1(12):1176-1187. PMC: 8054994. DOI: 10.1038/s43018-020-00126-z. View

Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum F, Buchner T . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2016; 129(4):424-447. PMC: 5291965. DOI: 10.1182/blood-2016-08-733196. View

10.

Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E . Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021; 11(2):41. PMC: 7900255. DOI: 10.1038/s41408-021-00425-3. View

11.

Tabe Y, Saitoh K, Yang H, Sekihara K, Yamatani K, Ruvolo V . Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine. Sci Rep. 2018; 8(1):16837. PMC: 6237992. DOI: 10.1038/s41598-018-35198-6. View

12.

Lv M, Wang Y, Chang Y, Zhang X, Xu L, Jiang Q . Myeloablative Haploidentical Transplantation Is Superior to Chemotherapy for Patients with Intermediate-risk Acute Myelogenous Leukemia in First Complete Remission. Clin Cancer Res. 2018; 25(6):1737-1748. DOI: 10.1158/1078-0432.CCR-18-1637. View

13.

Yu J, Xie M, Ge S, Chai P, Zhou Y, Ruan J . Hierarchical Clustering of Cutaneous Melanoma Based on Immunogenomic Profiling. Front Oncol. 2020; 10:580029. PMC: 7735560. DOI: 10.3389/fonc.2020.580029. View

14.

Myers J, Miller J . Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2020; 18(2):85-100. PMC: 8316981. DOI: 10.1038/s41571-020-0426-7. View

15.

De Sanctis J, Dumut D, Radzioch D, Hajduch M . Functionally Relevant Differences in Plasma Fatty Acid Composition and Expression of Cytotoxic and Inhibitory NK Cell Receptors between Healthy Young and Healthy Elder Adults. Nutrients. 2020; 12(12). PMC: 7759996. DOI: 10.3390/nu12123641. View

16.

Niu L, Wang Y, Wong C, Gao S, Mo X, Huang X . Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage. Transl Oncol. 2021; 14(9):101159. PMC: 8319687. DOI: 10.1016/j.tranon.2021.101159. View

17.

Eisfeld A, Kohlschmidt J, Mims A, Nicolet D, Walker C, Blachly J . Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years. Leukemia. 2020; 34(12):3215-3227. PMC: 7882079. DOI: 10.1038/s41375-020-0872-3. View

18.

Pyzer A, Stroopinsky D, Rajabi H, Washington A, Tagde A, Coll M . MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood. 2017; 129(13):1791-1801. PMC: 5813734. DOI: 10.1182/blood-2016-07-730614. View

19.

Choo S . The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J. 2007; 48(1):11-23. PMC: 2628004. DOI: 10.3349/ymj.2007.48.1.11. View

20.

Watson C, Cohain A, Griffin R, Chun Y, Grishin A, Hacyznska H . Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions. Nat Commun. 2017; 8(1):1943. PMC: 5715016. DOI: 10.1038/s41467-017-02188-7. View