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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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 1

Global DNA methylation status of the different iB-ALL subtypes.

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Global DNA methylation status of the different iB-ALL subtypes. (A) Viol...
(A) Violin plots reflecting the global DNA methylation levels of CpG sites identified by WGB-Seq. Graph represents the percentages of CpG methylation distribution of the genome segmented in 10 Kbp genomic windows. The DNA methylation status significantly differs among all iB-ALL subtypes and the average methylation of healthy BCPs. ***P < 0.001, 2-sided Wilcoxon’s rank sum test. (B) Circos-plot representation of DNA methylation levels along the genome. CpG methylation was averaged in 10 Mbp genomic windows and the average DNA methylation value for each iB-ALL subtype is represented as a histogram track. Inner lines identify MLL-AF4+ (blue) and MLL-AF9+ (green) translocation events. (C) Line plots depicting the DNA methylation profile for the FLT3 gene. The CpG context and the CpG site location are mapped to the corresponding genomic coordinates, as indicated in the lower panels. Areas with significant (q < 0.05) differential methylation between MLL-AF4+/MLL-AF9+ and non-MLLr iB-ALL or healthy BCPs methylomes are shaded. ***P < 0.001. (D) Venn diagrams representing the total number of DMRs with consistent hyper- or hypomethylation changes for each of the indicated comparisons. (E) Heatmap indicating the log2 odds ratio enrichment of different DNA repetitive regions for significant hyper- or hypomethylated DMRs, respectively (q < 0.05).