Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia

Abstract

Purpose: Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. Experimental Design: We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Results: We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic co-targeting of the synergistic key regulator pair STAT5B and BCL2-associated athanogene 1 (BAG1) significantly reduced leukemia cell viability in vitro. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Conclusions: Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.

Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity

“…We selected ARACNe 23,34 , GRNdb 15,30 , and DoRothEA 29 as representatives of different GRN reconstruction approaches – ARACNe is one of the longest-established methods and infers GRNs solely from transcriptomes; GRNdb is more recently developed and uses GENIE3 GRNs inferred from transcriptomes that are further refined with ChIP-Seq data; while DoRothEA contains curated GRNs that incorporate cis-regulatory information from ChIP-Seq peaks, literature curated resources, and TF binding motifs within promoters. For ARACNe and GRNdb, we obtained cancer type-specific GRNs, i.e., a breast cancer GRN was assembled from gene expression profiles of breast cancer samples, while for DoRothEA, only cancer type-agnostic GRNs were available.…”

Network controllability solutions for computational drug repurposing using genetic algorithms

“…On the experimental side, validating the predictions made by the network-based approaches would help drive this research line forward, and it would offer an insight into how to apply it to disease data. Some demonstrations already exist 19 , but more work is needed before the network analytics approach becomes a standard tool in this field. On the computational side, adding to the framework some quantitative aspects about the type and the weight of the interactions would help eliminate some of the false positive results.…”

“…Others, on the contrary, are known to be computationally difficult, yet approximate efficient solutions are still achievable 5 . Recent successful applications of network controllability include research on the contribution of individual neurons in the locomotion of C. elegans 18 , and on the discovery of potential drug combinations for leukemia 19 , breast cancer and COVID-19 20 .…”

The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

“…Using integrated genomic and transcriptomic analyses of 1046 childhood B-ALL cases, CIS has recently been identified as one of the synergistic key regulators in Philadelphia chromosome-like B-ALL (Ph-like B-ALL) [74]. Deletion of CIS in human pluripotent stem cell-derived natural killer cells (CIS -/-iPSC-NK) enhanced NK cell cytotoxic activity against K562 and Molm-13 AML cells.…”