Refining the relationship between gut microbiota and common hematologic malignancies: insights from a bidirectional Mendelian randomization study.

Background: The relationship between gut microbiota and hematologic malignancies has attracted considerable attention. As research progresses, it has become increasingly clear that the composition of gut microbiota may influence the onset and progression of hematologic malignancies. However, our understanding of this association remains limited. Methods: In our study, we classified gut microbiota into five groups based on information at the phylum, class, order, family, and genus levels. Subsequently, we obtained data related to common hematologic malignancies from the IEU Open GWAS project. We then employed a bidirectional Mendelian Randomization (MR) approach to determine whether there is a causal relationship between gut microbiota and hematologic malignancies. Additionally, we conducted bidirectional MR analyses to ascertain the directionality of this causal relationship. Results: Through forward and reverse MR analyses, we found the risk of lymphoid leukemia was significantly associated with the abundance of phylum Cyanobacteria, order Methanobacteriales, class Methanobacteria, family Peptococcaceae, family Methanobacteriaceae, and genera Lachnospiraceae UCG010, Methanobrevibacter, Eubacterium brachy group, and Butyrivibrio. The risk of myeloid leukemia was significantly associated with the abundance of phylum Actinobacteria, phylum Firmicutes, order Bifidobacteriales, order Clostridiales, class Actinobacteria, class Gammaproteobacteria, class Clostridia, family Bifidobacteriaceae, and genera Fusicatenibacter, Eubacterium hallii group, Blautia, Collinsella, Ruminococcus gauvreauii group, and Bifidobacterium. The risk of Hodgkin lymphoma was significantly associated with the abundance of family Clostridiales vadinBB60 group, genus Peptococcus, and genus Ruminococcaceae UCG010. The risk of malignant plasma cell tumor was significantly associated with the abundance of genera Romboutsia and Eubacterium rectale group. The risk of diffuse large B-cell lymphoma was significantly associated with the abundance of genera Erysipelatoclostridium and Eubacterium coprostanoligenes group. The risk of mature T/NK cell lymphomas was significantly associated with the abundance of phylum Verrucomicrobia, genus Ruminococcaceae UCG013, genus Lachnoclostridium, and genus Eubacterium rectale group. Lastly, the risk of myeloproliferative neoplasms was significantly associated with the abundance of genus Coprococcus 3 and Eubacterium hallii group. Conclusion: Our study provided new evidence for the causal relationship between gut microbiota and hematologic malignancies, offering novel insights and approaches for the prevention and treatment of these tumors.

A preparation method for mRNA-LNPs with improved properties.

The properties of mRNA lipid nanoparticles (mRNA-LNPs), including size, empty particles, morphology, storage stability, and transfection potency, are critically dependent on the preparation methods. Here, a Two-step tangential-flow filtration (TFF) method was successfully employed to improve the properties of mRNA-LNPs during the preparation process. This method involves an additional ethanol removal step prior to the particle fusion process. Notably, this innovative approach has yielded mRNA-LNPs with larger particles, a reduced proportion of empty LNPs, optimized storage stability (at least 6 months at 2-8 °C), improved in vitro transfection efficiency, and minimized distribution in the heart and blood in vivo. In summary, this study represents the implementation of the innovative Two-step TFF method in the preparation of mRNA-LNPs. Our findings indicate substantial enhancements in the properties of our mRNA-LNPs, specifically with regard to the percentage of empty LNPs, stability, transfection efficiency, and in vivo distribution. These improvements have the potential to optimize their industrial applicability and expand their clinical use.

JMJD1C Regulates Megakaryopoiesis in In Vitro Models through the Actin Network.

The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte-erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network.

The role of long noncoding RNA HOTAIR in the acquired multidrug resistance to imatinib in chronic myeloid leukemia cells.

OBJECTIVES: Imatinib, a breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, has revolutionized the treatment of chronic myelogenous leukemia (CML). However, the development of multidrug resistance (MDR) limits the clinical application of imatinib. In this study, we aimed to investigate the mechanisms of long noncoding RNA (lncRNA) HOTAIR in CML resistance to imatinib. METHODS: Thirty-four CML patients were divided into multidrug resistance protein 1 (MRP1)-low and MRP1-high groups according to the median expression. Real-time PCR (qPCR) was used to detect the expression of lncRNA HOTAIR in CML patients, and MTT assay and flow cytometry assay were employed to detect the biological function of silencing lncRNA HOTAIR on the cell survival rate and apoptotic rate. An imatinib-resistant human CML cell line K562 (K562-R) was established, and western blot was used to detect the impact of lncRNA HOTAIR on the activation of PI3K/Akt signaling pathway. RESULTS: Our results showed that lncRNA HOTAIR was greatly upregulated in the MRP1-high patients as well as in the K562-imatinib-resistant cells compared with control. Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the K562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3K/Akt was greatly attenuated when HOTAIR was knocked down in K562-imatinib cells. DISCUSSIONS: These data suggest that the knockdown of HOTAIR may play a crucial role in improving acquired resistance to imatinib in CML K562-R cells via PI3K/Akt pathway. CONCLUSIONS: LncRNA HOTAIR modulates CML cell MDR in a PI3K/Akt-dependent way.