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 predicated 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 (MLLr) and non-MLLr iB-ALL leukemias uniformly treated according to 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 co-expression 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.

Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy

“…In addition, we were only able to identify a small proportion of genes that were upregulated and located within hypomethylated regions following treatment. Our findings are supported by more recent studies, which indicate that the mechanisms for epigenetic regulation in infants with ALL extend beyond the classical model of methylation and gene expression and are more complex than previously thought [36,37].…”

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

“…A recent case review reporting the recurrent KMT2A-MLLT3 rearrangement in extremely rare mature B-ALL patients 38 also suggests an instructive preference of KMT2A-MLLT3 for B-lineage maturation. In addition, two recent DNA methylation profiling studies demonstrated relatively similar methylation profiles between KMT2A-MLLT3 and KMT2A -germline infants 39 , 40 , which may be due to the common pre-B state of KMT2A-MLLT3 and KMT2A -germline infant ALL. Furthermore, KMT2A-MLLT3 -driven infant ALL (IC4) exhibited a distinct profile of cooperating genetic alterations with frequent CNAs and mutations in PAX5 and cell cycle regulators ( CDKN2A/B and CCND3 ), indicating a unique pathogenesis of this subgroup among KMT2A -r infant ALL.…”

Microfluidic-based dynamic BH3 profiling predicts anticancer treatment efficacy

“…To avoid these phenotypic changes, other functional assays directly test compounds on patient-isolated cells. This strategy has been successfully implemented in hematological malignancies 48,49 , since the obtention of a large number of cells is possible 50,51 . Most of these initiatives focus on incubating patient cells with multiple drugs to study cytotoxicity after some days of treatment; using different assays such as MTS, CellTiter®, or Annexin V/propidium iodide staining [52][53][54][55] .…”