Soulier, J. | Search bioRxiv

bioRxiv2020

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). However, the genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyzed a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observed an average of 25-fold increase of mutation rates in XP-C vs. sporadic leukemia which we presume leads to its elevated incidence and early appearance. In all XP-C tumors predominant mutational process is characterized by a distinct mutational signature, highlighting a specific mutational pattern in the context of GG-NER deficiency. We observed a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients leading to internal cancers.

cancer biology↗

bioRxiv2019

A comprehensive dataset of TLX1 positive ALL-SIL lymphoblasts and primary T-cell acute lymphoblastic leukemias

Most currently available transcriptome data of T-cell acute lymphoblastic leukemia (T-ALL) are based on polyA[+] RNA sequencing methods thus lacking non-polyadenylated transcripts. Here, we present the data of polyA[+] and total RNA sequencing in the context of in vitro TLX1 knockdown in ALL-SIL cells and a primary T-ALL cohort. We extended this dataset with ATAC sequencing and H3K4me1 and H3K4me3 ChIP sequencing data to map putative gene regulatory regions. In this data descriptor, we present a detailed report of how the data were generated and which bioinformatics analyses were performed. Through several technical validations, we showed that our sequencing data are of high quality and that our in vitro TLX1 knockdown was successful. We also validated the quality of the ATAC and ChIP sequencing data and showed that ATAC and H3K4me3 ChIP peaks are enriched at transcription start sites. We believe that this comprehensive set of sequencing data can be reused by others to further unravel the complex biology of T-ALL in general and TLX1 in particular.

molecular biology↗