Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. Here, we perform comprehensive multi-omic analyses of 49 readily available childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. We connect the molecular phenotypes with drug responses to 528 oncology drugs, identifying drug correlations as well as lineage-dependent correlations. We also identify the diacylglycerol-analog bryostatin-1 as a therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activates pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data is the foundation for the interactive online Functional Omics Resource of ALL (FORALL) with navigable proteomics, transcriptomics, and drug sensitivity profiles at https://proteomics.se/forall.

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.

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Almost 50% of human, more than 50% of maize, and about 20% of Drosophila melanogaster genomes consist of transposable elements (TEs) (Haberer et al., 2005;Kannan et al., 2015;McCullers & Steiniger, 2017). TEs are DNA sequences that can be divided in LTR-retrotransposons, non-LTR-retrotransposons, and DNA transposons (Finnegan, 1992). TEs migrate and amplify in the genome by using insertion mechanisms (Gilbert et al., 2021). While retrotransposons only need to be expressed to become potentially active, DNA transposons require transposases for excision and reintegration (Lanciano & Cristofari, 2020). TEs may reintegrate essentially

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. To characterize ALL subtypes and identify novel pharmacologic vulnerabilities, we performed comprehensive multi-omic analyses of 49 widely-used childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. This enabled us to characterize the functional impact of genetic fusions and cellular differentiation states. The proteomics data revealed differences in spliceosome and p53 levels not evident in the transcriptomics data and with improved correlation to drug sensitivity. Focusing on BCP-ALL cell lines, we connected the genotype, molecular phenotype, and functional phenotype with drug response data on 528 oncology drugs. Here, we identified the DAG-analog Bryostatin-1 as a novel therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activated pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data also forms an interactive online resource with navigable proteomics, transcriptomics, and drug sensitivity profiles at https://lehtio-lab.se/forall/.