Acute myeloid leukemia

The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia

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Abstract

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64–6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38–8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63–7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16–7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.

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Acknowledgements

We thank all the patients, their families, and the staff of all the centers of Société Française des Cancers de l’Enfant (SFCE) for their implication in the trial. The results published here are in part based upon data generated by the TARGET initiative managed by the NCI. The AML Project data used for this analysis are available at https://ocg.cancer.gov/programs/target/data-matrix. More Information about TARGET can be found at http://ocg.cancer.gov/programs/target.

Funding information

This work was supported by the French National Cancer Institute (INCA-DGOS_5797) and by a grant from the French Ministry of Health (PHRC-K 2003 no 03142). The Trousseau laboratory received funding from the Association Laurette Fugain and La Fondation de France to support molecular study and the ELAM02 national tumor Bank. Integrated research program: pediatric cancer PAIR grant: CONECT-AML INCA PRT-K: CAMELIA.

Author information

GL was the principal investigator of the ELAM02 trial. AP, FG, BN, GM, AB, YB, GL enrolled patients in the study. AR ensured database management. ND, AMR, CP, and HL performed genetic analysis. SN, JW, and JD provided materials and protocols. ND, CV, FL, MF, MC performed Nanostring assay and analyzed data. AP and MC performed statistical analysis. ND, AB, NP, CP, and MC wrote the manuscript which was approved by all the authors.

Correspondence to Nicolas Duployez or Meyling Cheok.

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The authors declare that they have no conflict of interest.

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Duployez, N., Marceau-Renaut, A., Villenet, C. et al. The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia. Leukemia 33, 348–357 (2019) doi:10.1038/s41375-018-0227-5

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