Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia

Abstract

ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) which interact with AU-rich elements in the 3'UTR of mRNA, leading to mRNA degradation and translational repression. Mice lacking ZFP36L1 and ZFP36L2 during thymopoiesis develop a Notch1-dependent T cell acute lymphoblastic leukaemia (T-ALL). Prior to the onset of T-ALL, thymic development is perturbed with accumulation of cells which have passed through the β-selection checkpoint without first expressing T cell receptor β (TCR-β). Notch1 expression is increased in non-transformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interact with evolutionarily conserved AU-rich elements within the 3' untranslated region of Notch1 and suppress its expression. These data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.The development of T cells in the thymus proceeds through a series of developmental stages characterised by progressive rearrangement of the T cell receptor (TCR) genes and regulated by a series of developmental checkpoints. This ordered process is orchestrated by transcription factor networks which integrate environmental cues to initiate gene expression programs appropriate to the developmental stage of the thymocyte1 -3. However there is increasing recognition that gene expression during lymphocyte development is also subject to regulation by post-transcriptional mechanisms. These affect the half-life of mRNA though promotion or

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

“…The stability of ICOS mRNA, which is governed by the RBPs Roquin-1 and -2, restrains the differentiation of follicular helper T cells (29)(30)(31)(32)(33). The RBPs Zfp36l1 and Zfp36l2 suppress Notch1 mRNA stability, regulating normal thymocyte differentiation and preventing malignant transformation (34). However, most of these studies lack a genome-wide view, an important consideration given the complexity of the RNA-processing network and the need to differentiate between direct and indirect effects caused by the absence of an RBP.…”

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

“…Notably, all ZFP36L1/L2 double-knockout mice developed thymic tumors, and the majority also displayed other abnormalities, including splenomegaly and lymphadenopathy. 81 Interestingly, in these same mice, there was a block in B-cell development from the CD25 ϩ B220 ϩ stage (Figure 1), although presumably this was not B-cell intrinsic as deletion of ZFP36L1/L2 in these mice was under control of CD2-cre and CD2 is not expressed in B cells. 82 Consistent with their proapoptotic functions, members of the ZFP36 family have been implicated as tumor suppressors in solid tumors.…”

Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements

“…However, the functional significance of these motifs has remained unknown. Two paralogs of TTP exist in the human genome, BRF1 (also known as ZFP36L1 and Tis11b) and BRF2 (ZFP36L2, Tis11d), which, like TTP, promote degradation of ARE-containing mRNAs (Ciais et al 2004;Hodson et al 2010;Zhang et al 2013). These proteins share the conserved zinc finger and CIM domains with TTP, but lack the tetraproline motifs characteristic of TTP.…”