Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia
Juan Ramón Tejedor, Clara Bueno, Meritxell Vinyoles, Paolo Petazzi, Antonio Agraz-Doblas, Isabel Cobo, Raúl Torres-Ruiz, Gustavo F. Bayón, Raúl F. Pérez, Sara López-Tamargo, Francisco Gutierrez-Agüera, Pablo Santamarina-Ojeda, Manuel Ramírez-Orellana, Michela Bardini, Giovanni Cazzaniga, Paola Ballerini, Pauline Schneider, Ronald W. Stam, Ignacio Varela, Mario F. Fraga, Agustín F. Fernández, Pablo Menéndez
Juan Ramón Tejedor, Clara Bueno, Meritxell Vinyoles, Paolo Petazzi, Antonio Agraz-Doblas, Isabel Cobo, Raúl Torres-Ruiz, Gustavo F. Bayón, Raúl F. Pérez, Sara López-Tamargo, Francisco Gutierrez-Agüera, Pablo Santamarina-Ojeda, Manuel Ramírez-Orellana, Michela Bardini, Giovanni Cazzaniga, Paola Ballerini, Pauline Schneider, Ronald W. Stam, Ignacio Varela, Mario F. Fraga, Agustín F. Fernández, Pablo Menéndez
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Research Article Genetics Oncology

Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia

Abstract

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL–specific gene expression–correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient–derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.

Authors

Juan Ramón Tejedor, Clara Bueno, Meritxell Vinyoles, Paolo Petazzi, Antonio Agraz-Doblas, Isabel Cobo, Raúl Torres-Ruiz, Gustavo F. Bayón, Raúl F. Pérez, Sara López-Tamargo, Francisco Gutierrez-Agüera, Pablo Santamarina-Ojeda, Manuel Ramírez-Orellana, Michela Bardini, Giovanni Cazzaniga, Paola Ballerini, Pauline Schneider, Ronald W. Stam, Ignacio Varela, Mario F. Fraga, Agustín F. Fernández, Pablo Menéndez

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Figure 2

Identification of differentially methylated sites in iB-ALL subgroups.

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Identification of differentially methylated sites in iB-ALL subgroups. (...
(A) Schematic indicating the number of samples analyzed with the Human MethylationEPIC microarray platform. (B) PCA for 758,932 CpG sites across all samples included in the DNA methylation study. (C) Heatmap representation depicting the methylation status of the 10,000 most variable CpG sites (y axis) for the different iB-ALL samples, BCPs, and naive B cells (x axis). (D) Barplot displaying the number of common (black) and specific (colored) significantly hyper- or hypomethylated CpG sites observed in the indicated comparisons (FDR < 0.05, mean β difference > 0.25). Venn diagram represents the number of overlapping dmCpGs between naive B cells and iB-ALL (β > 0.25). dmCpGs overlapping naive B cells and iB-ALL samples were discarded for downstream analyses because they represent methylation changes naturally occurring during B cell differentiation. The inset shows the total number of hyper- and hypomethylated CpG sites observed in each condition. (E) Pairwise Pearson’s correlation analysis indicating the degree of similarity between the different sample groups. A total of 77,596 dmCpGs observed at any iB-ALL vs. BCP condition were used for proper comparisons, and all comparisons were statistically significant (P < 0.001).