RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis

Abstract

Alterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small cell lung cancer (SCLC), choroid plexus tumors and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional compensation between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation of rb1 and rbl1 by multiplex CRISPR/Cas9 genome editing in the true diploid Xenopus tropicalis to gain insight into these in vivo compensatory mechanisms. We show that while rb1 inactivation is sufficient to induce choroid plexus papilloma, combined rb1 and rbl1 inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimicking tp53 mutant X. tropicalis line, we demonstrate increased malignancy of retinoblastoma-mutant neural malignancies upon concomitant inactivation of tp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, the tp53 status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental set-up, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1 and generate new insights in functional compensation within the retinoblastoma protein family in suppressing pancreatic and specific neural cancers.

CYP2J19 mediates carotenoid colour introgression across a natural avian hybrid zone

“…The SNPs on chromosome 20 associated with crown score are located ~1–2 Mb from ASIP/RALY on zebra finch, which have been shown to function in plumage coloration (Wang et al, 2019). Those SNPs overlap several genes in zebra finch with no previously known function in pigmentation, specifically PHD finger protein 20 ( PHF2 0), chromodomain helicase DNA binding protein 6 ( CHD6 ) and homeobox protein TGIF2 , but also retinoblastoma‐like protein 1 ( RBL1 ), which has recently been shown to affect black skin pigmentation in mice (Naert et al., 2020). There were no chromosomes with more than two significant SNPs associated with crown chroma or wing bar percentage of yellow over black, but we did find a significant association with regions of the genome and supercilium score, associated with chromosome 4 (Table 1, Table ) with SNPs overlapping genes C4H20orf194 and potassium voltage‐gated channel interacting protein 4 ( KCNIP4 ).…”

“…Most other genes that significant SNPs overlapped with have no previously known function in pigmentation, except for RBL1, shown to affect skin pigmentation in mice (Naert et al, 2020).…”

“…Those SNPs were also 1–2 Mb away from the ASIP ‐ RALY block known to play a role in pigmentation (Nadeau et al., 2008), but were in a region of chromosome 20 associated with supraloral and post‐ocular plumage coloration in yellow‐rumped warbler Setophaga coronata (Brelsford et al., 2017). Most other genes that significant SNPs overlapped with have no previously known function in pigmentation, except for RBL1 , shown to affect skin pigmentation in mice (Naert et al., 2020).…”

“…We found that crown colour was signifi- The SNPs on chromosome 20 associated with crown score are located ~1-2 Mb from ASIP/RALY on zebra finch, which have been shown to function in plumage coloration (Wang et al, 2019). Those SNPs overlap several genes in zebra finch with no previously known function in pigmentation, specifically PHD finger protein 20 (PHF20), chromodomain helicase DNA binding protein 6 (CHD6) and homeobox protein TGIF2, but also retinoblastoma-like protein 1 (RBL1), which has recently been shown to affect black skin pigmentation in mice (Naert et al, 2020). There were no chromosomes with more than two Note: Only chromosomes with more than two significant SNPs are shown with associations to each trait because, based on the permutation test, we expect one false positive at −log 10 (p) > 6.…”

Comprehensive Analysis of HDAC Family Identifies HDAC1 as a Prognostic and Immune Infiltration Indicator and HDAC1-Related Signature for Prognosis in Glioma

“…Of note, HDAC1 was transcriptionally regulated by the nuclear factor of activated T cell (NFAT), which played a role in glioma stem cell growth and mesenchymal transition ( Song et al, 2020 ). Retinoblastoma transcriptional corepressor like 1 (RBL1), known for its modulation in the G1/S cell cycle, behaved oppositely and functioned as a tumor suppressor in a GBM model, conflicts of which could come from either the species’ differences or some other regulations unidentified ( Naert et al, 2020 ). RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) earned prestige for its fusion with Runt-related transcription factor 1 (RUNX1) in acute myeloid leukemia ( Beghini, 2019 ).…”