MALAT1 is a conserved long noncoding RNA whose expression correlates with many human cancers. However, its significance in immunity remains largely unknown. Here, we observe that MALAT1 is upregulated in lipopolysaccharide (LPS)-activated macrophages. Knockdown of MALAT1 increases LPS-induced expression of TNFa and IL-6. Mechanistically, MALAT1 was found to interact with NF-jB in the nucleus, thus inhibiting its DNA binding activity and consequently decreasing the production of inflammatory cytokines. Additionally, abnormal expression of MALAT1 was found to be NFjB-dependent. These findings suggest that MALAT1 may function as an autonegative feedback regulator of NF-jB to help fine-tune innate immune responses.
Chronic myeloid leukemia (CML), which is characterized by the Philadelphia translocation, which fuses breakpoint cluster region (BCR) sequences from chromosome 22 upstream of the Abelson murine leukemia viral oncogene homolog (ABL) on chromosome 9, requires specific and efficient treatment. The CRISPR/Cas9 system, with its mechanism of specific DNA complementary recognition by engineered guide RNA (gRNA), allows the development of novel therapeutics for CML. To achieve targeted therapy of CML with the CRISPR/Cas9 system, we encapsulated a CRISPR/Cas9 plasmid (pCas9) expressing gRNA targeting the overhanging fusion region of the BCR-ABL gene (pCas9/gBCR-ABL) with poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA)-based cationic lipid-assisted polymeric nanoparticles (CLANs), which specifically disrupted the CML-related BCR-ABL gene while sparing the BCR and ABL genes in normal cells. After intravenous injection, CLANs carrying pCas9/gBCR-ABL (CLANpCas9/gBCR-ABL) efficiently knocked out the BCR-ABL fusion gene of CML cells and improved the survival of a CML mouse model, indicating that the combination of the CRISPR/Cas9 system with nanocarriers is a promising strategy for targeted treatment of CML.
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