UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma

Xiaoxi Li,Mingxian Liu,Charlie Degui Chen,Yanli Zhang,Liting Zheng,Hai Jiang

doi:10.1038/s41467-018-05084-w

Abstract

To explain the excess cancer rate in males, several candidates for “escape from X-inactivation tumor-suppressor” (EXITS) were recently identified. In this report we provide direct experimental evidence supporting UTX’s role as an EXITS gene. Using a mouse lymphoma model, we show clear dosage effect of UTX copy number during tumorigenesis, which strongly supports the EXITS theory. Importantly, UTX deletion not only accelerates lymphomagenesis, it also strongly promotes tumor progression. UTX-knockout tumors are more aggressive, showing enhanced brain dissemination and formation of blood vessels. Efnb1 is overexpressed in UTX KO tumors and can lead to such phenotypes. In human patients, lymphomas with low UTX expression also express high levels of Efnb1, and cause significantly poor survival. Lastly, we show that UTX deficiency renders lymphoma sensitive to cytarabine treatment. Taken together, these data highlight UTX loss’s profound impacts on tumor initiation and drug response.

Highlights

To explain the excess cancer rate in males, several candidates for “escape from X-inactivation tumor-suppressor” (EXITS) were recently identified
Using hematopoietic stem cell (HSC) from surviving Ubiquitously transcribed tetratricopeptide repeat X-linked protein (UTX)−/Y mice, Ntziachristos et al showed that UTX deficiency in male HSCs accelerates Notch1-induced T cell acute lymphoblastic leukemia (T-ALL), when transplanted into recipient mice[10]
We showed that UTX loss promotes tumor formation, it strongly enhances the aggressiveness of lymphoma, as evidenced by brain dissemination and formation of blood vessels, through upregulation of Efnb[1]

Summary

Introduction

To explain the excess cancer rate in males, several candidates for “escape from X-inactivation tumor-suppressor” (EXITS) were recently identified. Another study, using similar ex vivo models, showed that shRNA-mediated knockdown of UTX accelerated Notch1-induced T-ALL11 These studies highlighted the tumor suppressor role of UTX during leukemogenesis. Through comprehensive analysis of gene mutation status of human cancers, several genes, including UTX, were recently identified as candidates for “escape from X-inactivation tumorsuppressor” (EXITS), which could explain the excess cancer incidence in males[13,14]. To stringently test this idea, we argue that it is necessary to employ tissue-specific UTX-knockout mice, so that the aforementioned dosage effect could be addressed with UTX+/− and UTX−/− female mice. We observed that UTX deficiency confers enhanced sensitivity to the anticancer drug cytarabine, suggesting possible approaches to targeting UTX-deficient tumors

Methods

Results

Conclusion