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 12

The AP-1 inhibitor T5224 synergistically cooperates with VXL to partially reduce leukemia aggressiveness in vivo using MLLr iB-ALL xenografts.

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The AP-1 inhibitor T5224 synergistically cooperates with VXL to partiall...
(A) In vivo experimental design of the preclinical MLLr iB-ALL PDX models treated with VXL alone or in combination with the T5224 inhibitor. MRD was evaluated in BM 1 week after completion of the 2 cycles of VXL-based chemotherapy (day 20). Subsequent relapses were monitored in BM, spleen, and PB. (B) BM leukemic engraftment determined before treatment (day 0) in order to equally randomize mice based on BM leukemic burden to receive VXL or VXL+T5224 treatment. (C) Dot plots monitoring MRD in BM 1 week after completion of the 2 cycles of VXL±T5224 (day 20). (D) Proportion of leukemic mice and levels of leukemic engraftment in BM, spleen, and PB at the end of the follow-up period (mice were sacrificed when blasts were detected in PB or at day 80). For all the graphs, horizontal black line represents the mean and dots represent individual animals. **P < 0.01, 1-sided Welch’s t test.