Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia
Juan Ramón Tejedor, … , Agustín F. Fernández, Pablo Menéndez
Juan Ramón Tejedor, … , Agustín F. Fernández, Pablo Menéndez
Published May 13, 2021
Citation Information: J Clin Invest. 2021;131(13):e138833. https://doi.org/10.1172/JCI138833.
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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 7

E2F and AP-1 interacting factors control the methylation status of downstream target motifs.

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E2F and AP-1 interacting factors control the methylation status of downs...
(A) Ideogram representing the genomic location of E2F5 expression–correlating dmCpG sites. n denotes the number of correlating dmCpGs identified with ELMER algorithm. (B) Boxplot depicting the average methylation of the significant E2F5 expression–correlating CpG probes across different groups. (C) Boxplot reflecting the expression of E2F5 in the indicated groups. (D) Scatter plot showing the correlation between average DNA methylation of E2F5 motif targets and the expression of E2F5. Colored dots: blue, BCP; red, MLL-AF4+; green, MLL-AF9+; yellow, non-MLLr. (E) Violin plots indicating the distribution of gene expression changes (log2 fold change of the indicated groups versus healthy BCPs) of target genes with E2F5 motifs obtained with ELMER algorithm.*P < 0.05; ***P < 0.001, 2-sided Wilcoxon’s rank sum test. All correlated genes with E2F5 motifs included in any of the iB-ALL subgroups were used for the representation of the B cell gene expression distribution. The “random” group includes a random sampling of the same number of genes included in the B cell group, but using the original gene expression matrix including all genes with detectable expression in the RNA-Seq data set. (F–J) Same as A–E, but for the TF FOSL2.