RNA Regulators in Leukemia and Lymphoma

Abstract

Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma. Furthermore, we will discuss the potential therapeutic strategies that are currently being studied to specifically target RBPs in these diseases.

Figure 1.

Overview of the main cellular stages of posttranscriptional regulation. A general pathway for several of the many intermediary steps of posttranscriptional regulation, including some RNA-binding proteins (RBPs) demonstrated to be involved in controlling these steps. The steps highlighted include splicing, nucleocytoplasmic transport, mRNA stability, and translation.

Figure 2.

RNA-binding proteins (RBPs) are essential players in leukemia and lymphoma. Overview of the main RBPs and their regulatory pathways discussed in this review. (A) Mutations in splicing factors SRSF2 and U2AF1 contribute to the myelodysplastic syndrome (MDS) through elevated R loops and replication stress. In human acute myeloid leukemia (AML) cells, RNA-binding motif protein 39 (RBM39) interacts with the spliceosome, including splicing factor 3 subunit b1 (SF3B1), and elevated RBM39 expression maintains efficient splicing of homeobox A9 (HOXA9) targets BMI1 and MYB, resulting in enhanced cell survival. (B) In human leukemia cells, high expression of methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) increases global N⁶-methyladenosine (m⁶A levels). Increased m⁶A on target genes MYC, MYB, PTEN, and BCL2 promotes their translation, which results in enhanced cell survival. (C) In B-cell lymphoma, MYC binds to the Lin28b promoter, which drives elevated LIN28B expression. LIN28B binds to the terminal loop of pre-let-7 microRNAs (miRNAs) and recruits terminal uridylyl transferase 4 (TUT4), leading to the uridylation and degradation of pre-let-7 miRNAs. Decreased levels of mature let-7 miRNAs result in increased levels of IL6 and MYC mRNA and elevated levels of high mobility group AT-hook 2 (HMGA2), Kirsten rat sarcoma viral oncogene homolog (KRAS), MYC, and IL6, resulting in enhanced cell survival. (D) In AML, overexpression of human antigen R (HuR) leads to increased stability of eIF4E transcripts and increased expression of eukaryotic initiation factor 4E (eIF4E). In lymphoma, elevated eIF4E expression results in efficient translation of MYC, cyclin-dependent kinase 6 (CDK6), MYB, BCL2, and NOTCH. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is highly expressed in lymphomas and leukemias, and in B-ALL cells, IGF2BP3 binds to the 3′ UTR of target transcripts, including MYC and CDK6, increases their stability, and maintains their efficient translation. (E) Musashi RNA-binding protein 2 (MSI2) and synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP) are highly expressed in leukemia and they coregulate the LSC gene expression program through the regulation of HOXA9 translation. MSI2 also binds to the transcripts MYC, IKZF2, FLT3, TSPAN3, and BCAT and promotes their translation, which results in increased cell survival.