Acute myeloid leukemia (AML) persistence and relapse are sustained by leukemia-propagating cells, yet the molecular programs supporting their expansion during disease evolution remain incompletely understood. Using serial patient-derived xenotransplantation, we establish a longitudinal model in which leukemia-initiating capacity progressively increases. Integrated single-cell transcriptomics and multi-omics profiling reveal a predominantly non-genetic trajectory that follows a conserved pattern across models and is associated with coordinated changes across epigenetic, transcriptional, and proteomic layers. Ribosome profiling and rRNA 2'-O-methylation analyses further support a stage-specific increase in translational activity with ribosome remodeling in advanced xenografts. A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML.
Clément Larrue, Paolo Angelino, Sarah Mouche et al.· Cell Reports Medicine· 0 citations
The ribosome, long considered an invariant actor of gene expression, recently emerged as a contributor to translational control through chemical modifications of ribosomal RNAs (rRNAs). These modifications are guided by small nucleolar RNAs (snoRNAs), which direct modifying enzymes to specific rRNA positions. Here, we report that lung adenocarcinoma (LUAD) cells that are resistant to tyrosine kinase inhibitors (TKIs) reshape both their translational program and rRNA 2’O-ribose methylation (2’Ome) profiles.
EML4-ALK
-positive LUAD cells that are resistant to crizotinib (ALK inhibitor) exhibit reduced global protein synthesis and a change in selective translation of mRNAs, encoding proteins previously linked to resistance. These cells show concomitant reduction in SNORD104 and 2’Ome at its associated 28S_Cm1327 position. Functional studies reveal that SNORD104 depletion abolishes 2’Ome at 28S_Cm1327 without affecting basal translation or cell viability, but enhances both under crizotinib exposure. Moreover, SNORD104 knockdown attenuates caspase activation and PARP cleavage during treatment, supporting reduced cell death. Altogether, our findings support a role for snoRNA-guided rRNA modification as a novel non-genomic mechanism in early adaptive responses to crizotinib therapy in LUAD.
Nour-El-Houda Mourksi, Caroline Isaac, J. Ripoll et al.· Cell Death & Disease· 0 citations
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