Integrative Network Analysis Reveals USP7 Haploinsufficiency Inhibits E-protein Activity in Pediatric T-lineage Acute Lymphoblastic Leukemia (T-ALL)

ABSTRACT: USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of >200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we show the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 shown accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Jurkat Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Timothy Shaw  

LAB HEAD: Jinghui Zhang

PROVIDER: PXD023377 | Pride | 2021-03-16

REPOSITORIES: Pride