Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI-resistance. Among extrinsic factors, cytokine-mediated TKI-resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34 + chronic phase (CP) CML
Primary resistance to tyrosine kinase inhibitors (TKI) is a significant barrier to optimal outcomes in chronic myeloid leukemia, but little is known about the factors contributing to response heterogeneity. Using scRNA-sequencing, we identified eight statistically significant features in pretreatment bone marrow mononuclear cells which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis transformation). Employing machine-learning, we also identified LSC and NK gene expression profiles predicting imatinib response with >80% accuracy, including zero false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor (ERP) expansion in vivo (p<0.05), and a marked 2-10-fold (6.3-fold in Group A vs 1.09-fold in Group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared to myeloid progenitors (p<0.001). These LSC features were lost with progressive resistance, and in patients who transformed, MYC- and IRF1-driven inflammatory regulons became evident. Patients with MMR also exhibited a 56-fold expansion (p<0.01) of a normally rare subset of hyperfunctional adaptive-like NK cells (CD57+NKG2C+) which diminished with progressive resistance, while patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance (through HLA-E binding on target cells). Finally, we developed a parsimonious set of antibodies to validate our scRNA-seq findings. This panel will be useful in prospective studies of primary resistance, and assessing the contribution of predetermined versus acquired factors in TKI response heterogeneity.
Enrichment of Veillonella parvula in the lung microbiota is strongly associated with non-small cell lung cancer (NSCLC) and induces the progression of lung adenocarcinoma in vivo, but its actual role and mechanism remain unexplored. This study analyzed the correlation between NSCLC and V. parvula abundance based on 16 s rRNA sequencing results. The effects of V. parvula on the progression of lung adenocarcinoma were observed in vivo and in vitro using a C57 bl/6j mouse tumor-bearing model, a bacterial cell co-culture model, combined with transcriptome sequencing, and a TCGA database to explore and validate the growth promotion of lung adenocarcinoma by V. parvula and its molecular mechanism. 16 s rRNA sequencing revealed that V. parvula was significantly enriched in lung adenocarcinoma. In vivo, V. parvula promoted the growth of lung adenocarcinoma in mice by suppressing the infiltration of tumor-associated T lymphocytes and peripheral T lymphocytes. It showed a higher affinity for lung adenocarcinoma in vitro and promoted lung adenocarcinoma cell proliferation through adhesion or intracellular invasion. Further analysis of differential gene expression and KEGG enrichment by transcriptome sequencing revealed that V. parvula induced CCN4 expression and activated NOD-like receptor and NF-κB signaling pathway in lung adenocarcinoma cells. Further analysis clarified that V. parvula promoted activation of the NF-κB pathway via Nod2/CCN4 signaling, which promoted lung adenocarcinoma cell proliferation. Thus, V. parvula mediates activation of the Nod2/CCN4/NF-κB signaling pathway to promote non-small cell lung adenocarcinoma progression, thereby providing a potential target for diagnosing and treating lung adenocarcinoma.
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