N 6 -methyladenosine (m 6 A) is a commonly present modification of mammalian mRNAs and plays key roles in various cellular processes. m 6 A modifiers catalyze this reversible modification. However, the underlying mechanisms by which these m 6 A modifiers are regulated remain elusive. Here we show that expression of m 6 A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesis of human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemia stem cell (LSC) function but is dispensable for normal hematopoiesis. Mechanistically, KDM4C regulates ALKBH5 expression via increasing chromatin accessibility of ALKBH5 locus, by reducing H3K9me3 levels and promoting recruitment of MYB and Pol II. Moreover, ALKBH5 affects mRNA stability of receptor tyrosine kinase AXL in an m 6 Adependent way. Thus, our findings link chromatin state dynamics with expression regulation of m 6 A modifiers and uncover a selective and critical role of ALKBH5 in AML that might act as a therapeutic target of specific targeting LSCs.
RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes, and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are a group of intracellular pathogen recognition receptors (PRRs) that play key roles in pathogen recognition and subsequent activation of innate immune signalling pathways. Expressions of several NLR subfamily members, including NOD1, NOD2, NLR-C3, NLR-C5 and NLR-X1 have been reported in many different teleost fish species. These receptors are activated by a variety of ligands, including lipopolysaccharides (LPS), peptidoglycans (PGN) and polyinosinic-polycytidylic acid [Poly(I:C)]. Synthetic dsRNA and bacterial or viral infections are known to stimulate these receptors both in vitro and in vivo. In this review, we focus on the identification, expression and function of teleost NLRs in response to bacterial or viral pathogens. Additionally, NLR ligand specificity and signalling pathways involved in the recognition of bacterial or viral stimuli are also summarized. This review focuses on current knowledge in this area and provides future perspectives regarding topics in need of additional investigation. Understanding the response of innate immune system to bacterial or viral infections in diverse species could inform the development of more effective therapies and vaccines.
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