bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2025.12.24.696467

Transcriptomic Profiling Reveals Key Molecular Events and Pathways Driving Acquired Chemotherapy Resistance in Relapsed Acute Myeloid Leukemia

Hu, J.·Wan, B.·Shi, J.·Zou, M.·He, C.
View original source ↗Export metadata ↓

Abstract

BackgroundAcute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy. Although induction therapy induces remission in many patients, relapse and acquired chemoresistance remain the major causes of treatment failure. Defining the molecular mechanisms underlying relapse is essential for improving therapeutic strategies. MethodsBone marrow samples from nine AML patients were analyzed, including five newly diagnosed cases and four relapsed cases after chemotherapy. Transcriptome sequencing and integrative bioinformatics analyses were performed, including differential expression analysis, GO/KEGG enrichment, GSEA, and protein-protein interaction (PPI) network analysis, to delineate relapse-associated molecular alterations. ResultsPrincipal component analysis demonstrated clear transcriptional segregation between primary and relapsed AML, indicating extensive molecular reprogramming during relapse. A total of 2,025 differentially expressed genes were identified, enriched in pathways related to epithelial-mesenchymal transition-like programs, leukemia stem cell maintenance, apoptosis evasion, and bone marrow microenvironment remodeling. Marked upregulation of FOXC1, HOXA11/HOXA11-AS, and AXL suggests key roles in sustaining stemness and promoting drug resistance. GO/KEGG analysis revealed coordinated activation of small GTPase, Rho/Ras signaling, ion transport, and epigenetic regulatory pathways, reflecting multilayered adaptive responses. GSEA indicated metabolic-epigenetic reprogramming in relapsed AML, while primary AML showed enrichment of energy metabolism and chromatin assembly pathways. PPI network analysis highlighted a central inflammation-metabolism axis involving TP53, IL6, CXCL8, and CCL2, associated with apoptosis resistance and metabolic adaptation. ConclusionsRelapsed AML is characterized by transcriptional reprogramming, metabolic remodeling, and microenvironment-driven adaptive resistance. Targeting small GTPase signaling, AXL, or IL6-related inflammatory pathways, alone or combined with epigenetic modulators, may offer promising therapeutic strategies to overcome chemoresistance in AML.

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hu, J., Wan, B., Shi, J., Zou, M., He, C.. 2025-12-26. Transcriptomic Profiling Reveals Key Molecular Events and Pathways Driving Acquired Chemotherapy Resistance in Relapsed Acute Myeloid Leukemia. https://doi.org/10.64898/2025.12.24.696467

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity

The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.

cell biology↗
bioRxiv2026

Nucleosome Core Allostery Governs Chromatin Recognition and Cell Fate

Nucleosomes regulate chromatin folding, accessibility, and factor recruitment. Current models primarily attribute these functions to histone tail modifications, while the core is largely viewed as a structural scaffold. Yet subtle changes within the nucleosome core can produce profound functional consequences, and the mechanisms underlying these effects remain unclear. Here, we describe nucleosome core allostery as a fundamental principle of chromatin regulation that amplifies the impact of minimal nucleosome variations. Leveraging natural differences between H2A.Z variants, we show that the nucleosome core encodes distinct conformational dynamics that propagate allosterically, thereby controlling nucleosome accessibility and recognition by chromatin factors. As a result, a single buried amino acid substitution alone is sufficient to reprogram nucleosome dynamics and bias cell identity. Our findings establish the nucleosome core as an allosteric regulatory module and provide a generalizable framework for how subtle variation within nucleosomes is amplified into diverse biological outcomes in development and disease.

cell biology↗
bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗