Abstract
Aberrant chromosomal translocations leading to tumorigenesis have been ascribed to the heterogeneously oncogenic functions. However, how fusion transcripts exporting remains to be declared. Here, we showed that the nuclear speckle-specific long noncoding RNA MALAT1 controls chimeric mRNA export processes and regulates myeloid progenitor cell differentiation in malignant hematopoiesis. We demonstrated that MALAT1 regulates chimeric mRNAs export in an m6A-dependent manner and thus controls hematopoietic cell differentiation. Specifically, reducing MALAT1 or m6A methyltransferases and the ‘reader’ YTHDC1 result in the universal retention of distinct oncogenic gene mRNAs in nucleus. Mechanically, MALAT1 hijacks both the chimeric mRNAs and fusion proteins in nuclear speckles during chromosomal translocations and mediates the colocalization of oncogenic fusion proteins with METTL14. MALAT1 and fusion protein complexes serve as a functional loading bridge for the interaction of chimeric mRNA and METTL14. This study demonstrated a universal mechanism of chimeric mRNA transport that involves lncRNA-fusion protein-m6A autoregulatory loop for controlling myeloid cell differentiation. Targeting the lncRNA-triggered autoregulatory loop to disrupt chimeric mRNA transport might represent a new common paradigm for treating blood malignancies.
Highlights
Genomic alterations, aberrant chromosomal translocations, are responsible for the onset of many types of cancers[1,2], such as leukemia
For univariate and multivariate analyses of prognostic factors, a Cox proportional hazard regression model was used. p < 0.05 was considered statistically significant. Both the mRNA and fusion proteins resulting from chromosomal rearranged genes were hijacked in nuclear speckles by MALAT1 To determine if there are any regulatory RNAs or other molecules that fusion proteins directly interact with, we used the PML-RARα fusion protein as a model, which is a specific t(15;17) chromosomal translocation resulting in the fusion of the promyelocytic gene (PML) and the retinoic acid receptor alpha gene (RARA) into the oncoprotein PML-RARA3,4
It is the first to report that these fusion proteins were found to be located in nuclear speckles and physically interact with m6A methyltransferases (e.g., methyltransferase-like 3 (METTL3), METTL14, and Wilms’ tumor 1-associating protein (WTAP)) through the long noncoding RNA (lncRNA) MALAT1, an important regulatory component of the RNA–protein complex in nuclear speckles
Summary
Aberrant chromosomal translocations, are responsible for the onset of many types of cancers[1,2], such as leukemia. PMLRARα (t15; t17)[3,4], MLL fusions (t11)[5,6,7], and AML1-ETO (t8; t21)[8,9,10] are typical oncogenic fusion genes that contribute to particular subtypes of leukemogenesis How these rearrangements can lead to tumorigenesis has traditionally been explained by their ability to encode and express proteins; such proteins are commonly referred to as oncogenic ‘fusion proteins’[2,11], indicating that the regulation of mRNA export of fusion proteins is important for oncogenic protein expression. A greater understanding of the mRNA export process of chromosomal translocations resulting in fusion genes is especially important for clinical therapeutic drug development[11,13]
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