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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.

 Autoría: Tejedor J.R., Bueno C., Vinyoles M., Petazzi P., Agraz-Doblas A., Cobo I., Torres-Ruiz R., Bayón G.F., Pérez R.F., López-Tamargo S., Gutierrez-Agüera F., Santamarina-Ojeda P., Ramírez-Orellana M., Bardini M., Cazzaniga G., Ballerini P., Schneider P., Stam R.W., Varela I., Fraga M.F., Fernández A.F., Menéndez P.,

 Fuente: The Journal of Clinical Investigation, 2021, 131(13), e138833

 Editorial: American Society for Clinical Investigation

 Año de publicación: 2021

 Nº de páginas: 56

 Tipo de publicación: Artículo de Revista

 DOI: 10.1172/JCI138833

 ISSN: 0021-9738,1558-8238

 Proyecto español: SAF-2019-108160-R ; SAF2016-76758-R

 Url de la publicación: https://www.doi.org/10.1172/JCI138833

Autoría

TEJEDOR, JUAN RAMÓN

BUENO, CLARA

VINYOLES, MERITXELL

PETAZZI, PAOLO

ANTONIO MANUEL AGRAZ DOBLAS

COBO, ISABEL

TORRES-RUIZ, RAÚL

BAYÓN, GUSTAVO F.

PÉREZ, RAÚL F.

LÓPEZ- TAMARGO, SARA

GUTIERREZ-AGÜERA, FRANCISCO

SANTAMARINA-OJEDA, PABLO

RAMÍREZ- ORELLANA, MANUEL

BARDINI, MICHELA

CAZZANIGA, GIANNI

BALLERINI, PAOLA

SCHNEIDER, PAULINE

STAM, RONALD W.

FRAGA, MARIO F.