A 4-gene prognostic index for enhancing acute myeloid leukaemia survival prediction

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Ortiz Rojas, Cesar Alexander ; Pereira-Martins, Diego Antonio ; Bellido More, Candy Christie ; Sternadt, Dominique ; Weinhauser, Isabel ; Hilberink, Jacobien R. ; Coelho-Silva, Juan Luiz ; Thome, Carolina Hassibe ; Ferreira, Germano Aguiar ; Ammatuna, Emanuele ; Huls, Gerwin ; Valk, Peter J. ; Schuringa, Jan Jacob ; Rego, Eduardo Magalhaes

• Document type: Journal article
• Source: British Journal of Haematology; v. 204, n. 6, p. 14-pg., 2024-04-23.

Abstract

Despite advancements in utilizing genetic markers to enhance acute myeloid leukaemia (AML) outcome prediction, significant disease heterogeneity persists, hindering clinical management. To refine survival predictions, we assessed the transcriptome of non-acute promyelocytic leukaemia chemotherapy-treated AML patients from five cohorts (n = 975). This led to the identification of a 4-gene prognostic index (4-PI) comprising CYP2E1, DHCR7, IL2RA and SQLE. The 4-PI effectively stratified patients into risk categories, with the high 4-PI group exhibiting TP53 mutations and cholesterol biosynthesis signatures. Single-cell RNA sequencing revealed enrichment for leukaemia stem cell signatures in high 4-PI cells. Validation across three cohorts (n = 671), including one with childhood AML, demonstrated the reproducibility and clinical utility of the 4-PI, even using cost-effective techniques like real-time quantitative polymerase chain reaction. Comparative analysis with 56 established prognostic indexes revealed the superior performance of the 4-PI, highlighting its potential to enhance AML risk stratification. Finally, the 4-PI demonstrated to be potential marker to reclassified patients from the intermediate ELN2017 category to the adverse category. In conclusion, the 4-PI emerges as a robust and straightforward prognostic tool to improve survival prediction in AML patients. Although genetic markers have advanced the prediction of outcomes for acute myeloid leukaemia (AML), the complex variability of the disease continues to challenge its clinical management. In this study, AML patients are stratified using a 4-gene prognostic index (4-PI) derived from transcriptome analysis across five distinct cohorts. The 4-PI, comprising CYP2E1, DHCR7, IL2RA and SQLE, categorizes patients into groups with differential prognoses, revealing that a high 4-PI is associated with TP53 mutations and a signature of cholesterol biosynthesis. Furthermore, high 4-PI cells show an enrichment for leukaemia stem cell markers. Validation through in silico analysis and quantitative PCR across multiple cohorts, including paediatric cases, demonstrates the 4-PI's robustness and its potential for clinical application. Notably, the 4-PI outperforms 56 other prognostic indices and may reclassify patients within the intermediate-risk category of ELN2017 guidelines to an adverse prognosis, thereby providing a more nuanced approach to AML treatment stratification.image (AU)

• FAPESP's process: 23/02952-0 - Identification and functional characterization of macrophages subpopulations associated with resistance to anthracycline and cytarabine in acute myeloid leukemia through single-cell multiomic analysis
• Grantee: César Alexander Ortiz Rojas
• Support Opportunities: Scholarships in Brazil - Post-Doctoral