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 9

MLL-AF4 regulates the expression of AP-1 members and RUNX1 and reshapes the methylome landscape of CD34+ cells.

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MLL-AF4 regulates the expression of AP-1 members and RUNX1 and reshapes ...
(A) Boxplot depicting the average expression of E2F5, FOSL2, andRUNX1 genes in healthy untransduced CD34+ cells or in CD34+ cells transduced with either human:murine chimeric MLL-AF4 or human MLL-AF9. ***P < 0.001, 2-sided Welch’s t test. n = 3; n = 6; n = 3, respectively. (B) UCSC Genome Browser tracks representing the binding pattern of MLL-AF4 (in CD34+ cells) or MLLN/AF4C (in SEM cells) in the vicinity of E2F5, FOSL2, or RUNX1 genes. Data represents ChIP-Seq signals obtained from NCBI database Gene Expression Omnibus [GEO] GSE84116 and GSE74812, respectively. (C) Barplots indicating RT-PCR relative fold-change of E2F5, FOSL2, or RUNX1 expression between nonedited CD34+ cells (CD34control) and CRISPR-edited CD34+ cells carrying locus-specific t(4;11)/MLL-AF4+ (CD34CRISPR t(4;11)). Barplots represent mean± SD. *P < 0.05, 2-sided Welch’s t test. (D) Scatterplot indicating the number of hyper- or hypomethylated CpG sites observed upon CRISPR t(4:11)/MLL-AF4+ edition in CD34+ cells (mean β difference > 0.20). (E) Venn diagrams representing the number of overlapping genes decorated with dmCpGs (top) or the number of overlapping dmCpGs (bottom, positional overlap) between MLL-AF4+ patients and CD34+ t(4;11)/MLL-AF4+ (CD34CRISPR t(4;11)) cells, as compared with healthy BCPs or nonedited CD34+ cells, respectively. P < 0.001. One-tailed hypergeometric test was used for all the comparisons. (F) Plots displaying enrichment of TFBS in the context of hypo- and hypermethylated CpGs in CD34+ t(4;11)/MLL-AF4+ (CD34CRISPR t(4;11)) cells as determined by the information obtained from the GTRD database. The y axis represents the –log10 adjusted P value enrichment of particular TFBS data set as compared with the background distribution of the EPIC platform.