Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

Abstract

Ribosomal protein (RP) mutations in diseases such as 5q؊ syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ϳ 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk. (Blood. 2012;120(18):3764-3773) IntroductionIn addition to their role as structural components of ribosomes, ribosomal proteins (RPs) are increasingly understood to play critical roles in development and disease, in some cases from outside of the ribosome. These include roles in regulation of cell-cycle progression, apoptosis, 1 and translation, through direct interactions with mRNA. 2 Mutations in RPs cause diseases collectively termed ribosomopathies, which include myelodysplastic syndromes (MDS) and diamond blackfan anemia (DBA). DBA is caused by mutations in a variety of RPs, with approximately one-half of all cases resulting from mutations in RPS19, RPS26, RPL5, and RPL11, whereas a type of myelodysplastic syndrome known as 5qϪ syndrome has been attributed to the monoallelic loss of RPS14. 3,4 RPS14 haploinsufficiency in 5qϪ syndrome, as well as the ribosome dysfunction observed in other bone marrow failure syndromes, is associated with increased risk in patients for the development of hematologic malignancies. 5 Observations in animal models have similarly linked RP gene mutations with alterations in cancer risk because loss of one copy of numerous, essential RP genes increased susceptibility to tumor formation in zebrafish, 6 suggesting that some RPs may serve as haploinsufficient tumor suppressors. Nevertheless, neither the basis by which RP function as tumor suppressors nor the way RP mutations predispose to malignancy has been explained.The ribosomal protein L22 (Rpl22) is an RNA-binding component of the 60S ribosomal subunit that is not thought to be required for global cap-dependent translation, but its normal physiologic role is poorly understood. We have determined that despite the ubiquitous expression of Rpl22, its germline ablation in mouse is not lethal, unlike ablation of most RP genes. 7,8 Instead, mice in which the Rpl22 gene is biallelically inactivated in the germline are viable, fertile, and grossly normal, with the only striking defect being an exquisitely specific block in the development ...

Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

“…Mutations within ribosomal genes have been identified in various syndromes or inherited conditions, mainly affecting the erythroid lineage (eg, DiamondBlackfan anemia); however, mutations within RPL5, RPL10, and RPL22 were recently reported in T-cell acute lymphoblastic leukemia. 33,34 Prompted by our findings, we screened a larger number of cases to not only obtain deeper insights into the frequency of RPS15 in CLL, but also, for the first time, to investigate their association with clinicobiological features and their impact on disease outcome. In the adverse prognostic patient group (mainly comprising U-CLL), we found that 6% of patients carried RPS15 mutations, of which one-third (11/36) also harbored TP53 aberrations; on the other hand, no RPS15 mutations were detected in the more favorable prognostic, IGHV-mutated CLL.…”

Modulation of Gene Expression Regulated by the Transcription Factor NF-κB/RelA

“…Nevertheless, there is indirect evidence of an interaction including that both ATP5C1 and RelA were reported to interact with mediator complex subunit 15 (MED15/ARC105), an RNA polymerase II transcription cofactor activity involved in transcription initiation. These interactions were detected by yeast two-hybrid and pulldown assays, respectively, in Stelzl et al (64) and Näär et al (65). In a recent study of the transcriptional response to relaxation training, ATP5C1 was one of the top up-regulated critical molecule, and served as a hub in the interactive network of the relaxation response-affected pathway.…”

LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7

“…LIN28A or LIN28B expression is associated with chronic myelogenous leukemia (CML), hepatocellular carcinoma, neuroblastoma, and cancers of the lung, breast, ovary, cervix, colon, and rectum King et al 2011a,b;Diskin et al 2012;Molenaar et al 2012). In addition, LIN28B expression is elevated or ectopically expressed in Wilm's tumors ), prostate cancer (Iliopoulos et al 2009), and T-acute lymphoblastic leukemias (T-ALLs) (Rao et al 2012). In cell lines, LIN28A or LIN28B are necessary and sufficient for promoting proliferation, soft agar colony formation, migration, invasion, and metastasis in xenograft mouse models (Iliopoulos et al 2009;Viswanathan et al 2009;King et al 2011b).…”