Li and colleagues report the genomic landscape of over 100 patients with relapsed acute lymphoblastic leukemia. Analysis of diagnosis-relapse-remission trios suggest that whereas early relapse is mediated by retained subclones, late relapse is driven by mutations induced by and conferring resistance to chemotherapy.

Microphthalmia, anophthalmia and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used SNP homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous micro-anophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalised and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid synthesis, suggesting that diminished retinoic acid levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS.

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Background and Aims Cancer is typically considered as a genetic and epigenetic disease. Although numerous studies have indicated that an aberrant structure, function, or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)‐induced hepatocellular carcinoma (HCC) remains unknown. Approach and Results In this study, we found that the WD repeat domain 5 protein (WDR5)—a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification—is highly expressed in HBV‐related HCC and promotes HCC development. WDR5 plays a critical role in HBV‐driven cell proliferation and tumor growth in mice, and the WDR5‐0103 small‐molecule inhibitor of WDR5 activity compromises HBV‐ and hepatitis B x protein (HBx)‐driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve HBx through its stabilization of the WDR5 protein by inhibiting the interaction between the damage‐specific DNA‐binding protein 1/cullin‐4 and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome wide and promotes genome‐wide H3K4me3 modification by means of WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5 through its α‐helix domain. WDR5 was also found to promote HBV transcription through H3K4 modification of covalently closed circular DNA minichromosome, and WDR5‐0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor‐promoting function in a WDR5‐dependent manner. Conclusions Our data reveals that WDR5 is a key epigenetic determinant of HBV‐induced tumorigenesis and that the HBx‐WDR5‐H3K4me3 axis may be a potential therapeutic target in HBV‐induced liver pathogenesis.