The molecular landscape of the C1498 murine acute myeloid leukemia cell line.

The murine C1498 cell line is one of the most widely used syngeneic models to investigate acute myeloid leukemia (AML) pathogenesis, tumor-host interactions and therapeutic responses. However, in the absence of a comprehensive molecular characterization it remains impossible to reliably associate genetic lesions with disease phenotype, drug sensitivity or resistance. Here, we provide an integrated genomic and functional analysis combining whole genome and whole transcriptome sequencing (WGS and WTS), multicolor fluorescent in situ hybridization (M-FISH) and drug sensitivity assays. WGS identified 2,007 coding variants absent from population databases, including functionally relevant alterations in AML-related genes. These comprised deleterious or likely pathogenic variants in Nf1, Gnas and Trp53 (murine ortholog of the human TP53 gene), a splice-site mutation in Crebbp and truncating variants in Bcor and Tet2. Structural variant analysis revealed 1,767 events, including deletions of Trp53, Nf1, Brca1, Csnk1a1, Ctnna1, Luc7l2 and cohesin genes, and Myc tandem duplication. Copy number variant profiling detected ten tumor-specific alterations, including amplifications of Stk32b and Bub1, the latter linked to aggressive cancer phenotypes. Variants integration uncovered biallelic disruption of Trp53, double-hit events affecting additional tumor suppressors (mutation and deletion: Nf1, Recql4) and oncogenes (mutation and amplification: Idh1, Gnas, Pik3cd, Vav1). Functionally, C1498 demonstrated in vitro a dose- and time-dependent response to venetoclax/azacitidine consistent with resistance, in line with the presence of altered Trp53 and recent prognostic AML signatures. This comprehensive molecular framework establishes C1498 as a genetically defined AML model and provides a valuable resource to inform biomarker-driven preclinical studies and translational research aimed at overcoming venetoclax/azacitidine resistance.