hnRNP L‐dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma

The human nonsense‐mediated mRNA decay pathway (NMD) performs quality control and regulatory functions within complex post‐transcriptional regulatory networks. In addition to degradation‐promoting factors, efficient and accurate detection of NMD substrates involves proteins that safeguard normal mRNAs. Here, we identify hnRNP L as a factor that protects mRNAs with NMD‐inducing features including long 3′UTRs. Using biochemical and transcriptome‐wide approaches, we provide evidence that the susceptibility of a given transcript to NMD can be modulated by its 3′UTR length and ability to recruit hnRNP L. Integrating these findings with the previously defined role of polypyrimidine tract binding protein 1 in NMD evasion enables enhanced prediction of transcript susceptibility to NMD. Unexpectedly, this system is subverted in B cell lymphomas harboring translocations that produce BCL2:IGH fusion mRNAs. CRISPR/Cas9 deletion of hnRNP L binding sites near the BCL2 stop codon reduces expression of the fusion mRNAs and induces apoptosis. Together, our data indicate that protection by hnRNP L overrides the presence of multiple 3′UTR introns, allowing these aberrant mRNAs to evade NMD and promoting BCL2 overexpression and neoplasia. While several factors are known to trigger mRNA degradation by nonsense‐mediated decay (NMD), binding of hnRNP L near stop codons allows mRNAs to evade turnover by NMD. Such evasion is widespread throughout the transcriptome but may be deleterious when aberrant transcripts are protected such as in B cell lymphomas by stabilising BCL2 fusion transcripts. While several factors are known to trigger mRNA degradation by nonsense‐mediated decay (NMD), the RNA‐binding protein hnRNP L protects NMD targets, a role that may turn malignant in B cell lymphomas by stabilising BCL2 fusion transcripts.