RNA binding proteins in MLL-rearranged leukemia

Abstract

RNA binding proteins (RBPs) have recently emerged as important post-transcriptional gene expression regulators in both normal development and disease. RBPs influence the fate of mRNAs through multiple mechanisms of action such as RNA modifications, alternative splicing, and miR-mediated regulation. This complex and, often, combinatorial regulation by RBPs critically impacts the expression of oncogenic transcripts and, thus, the activation of pathways that drive oncogenesis. Here, we focus on the major features of RBPs, their mechanisms of action, and discuss the current progress in investigating the function of important RBPs in MLL-rearranged leukemia.

Keywords: Leukemia; MLL; RNA binding protein.

Fig. 1

MLL mechanism of transformation. Wild-type (WT) MLL targets important transcriptional regulators of the hematopoietic system. Normal homeotic gene expression depends on the tightly regulated pause and release of RNA Polymerase II (RNA Pol II) on these MLL target genes. Many leukemia associated MLL fusion proteins such as MLL-AF4 recruit the super elongation complex (SEC). This recruitment leads to the premature release of paused RNA Pol II and activation of transcriptional elongation, leading to the aberrant gene expression of MLL target genes that drive leukemogenesis

Fig. 2

Post-transcriptional gene expression regulation by RBPs. RBPs are responsible for the regulation of the processing and fate of mRNAs. RBPs influence the localization, stability, degradation, and translation of mRNAs through multiple mechanisms of action. RBPs have been shown to have roles in RNA modifications, alternative splicing, the formation of ribonucleoprotein complexes (RNPs), microRNA (miR) mediated regulation of transcripts and miR biogenesis through association with the RNA induced silencing complex (RISC)

Fig. 3

RBP mechanisms of action. The major functions of RBPs include: (1) RNA processing through RNA modifications, RNA editing, alternative splicing, and noncoding RNA biogenesis such as microRNAs (miRs) and circular RNAs (circRNAs). (2) Transport and localization of mRNA through messenger ribonucleoprotein (mRNP) complexes, (P) bodies, and stress granules. (3) Stability and translation of mRNA through mRNP complexes, stress granules, RNA modifications, RNA editing, and binding at the 5′ untranslated region (UTR), coding sequence (CDS), and 3′ UTR. (4) Decay of mRNA through RNA modifications, P-bodies, and miR-mediated regulation and the interaction of the RNA induced silencing complex (RISC). (5) Multiple functions including any of the previously mentioned mechanisms in 1–4. All of these functions critically impact mRNA isoform expression, structure, stability, translation, and decay

Fig. 4

Post-transcriptional gene expression regulation by RBPs directly assessed in MLL-r leukemia. METTL3 and METTL14 function as m⁶A writers, FTO and ALKBH5 function as m⁶A erasers, and YTHDF2 functions as an m⁶A reader. ADAR1 catalyzes A-to-I RNA editing. RBPs involved in alternative splicing include the trans-acting splicing factor RBM39, the 5′ cap binding enzyme DCPS, and MBNL1. NCL has been shown to bind to the 3′UTR of mRNA transcripts and be required for miR biogenesis. ZFP36L1 binds to the 3′UTR of mRNA transcripts such as CDK6. DROSHA has been implicated to be recruited by MLL-AF4 and MLL-AF9 to target genes encoding miRs as well as function in the cytoplasm in non-canonical miR biogenesis. The METTL1/WDR4 heterodimeric complex catalyzes m⁷G modifications on tRNA. Multifunctional RBPs: LIN28B localizes in P-bodies, stress granules, and mRNP complexes and has an important function in miR biogenesis. MSI2 has been shown to bind to the 3′UTR of mRNA transcripts and interact with SYNCRIP to target the same transcripts. MSI2 may also have a function in alternative splicing. IGF2BP3 has been shown to function in alternative splicing, RNA modifications as an m⁶A reader, localization within ribonucleoprotein complexes (RNPs) and stress granules, and binding to the 3′ untranslated region (3′UTR) of mRNA transcripts impacting their association with the RNA induced silencing complex (RISC) to regulate the stability, translation, and degradation of target transcripts