Identification of USP9X as a leukemia susceptibility gene

Abstract

We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5kb de novo heterozygous in-frame deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n=42) demonstrated that MRXS99F probands with B-ALL (n=3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results (SEER) database (P<0.0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. Conversely, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females and expression levels are comparable in leukemia samples from both sexes (P=0.54) with the highest expressors being female patients with extra copies of X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes with low expression associated with poorer survival in high-risk B-ALL patients.

Roles of USP9X in cellular functions and tumorigenesis (Review)

“…USP9X also exerts negative effects in hematological malignancies by acting as a tumor suppressor gene. USP9X has been identified as a novel leukemia susceptibility gene associated with B-cell acute lymphoblastic leukemia (B-ALL) and multiple neurodevelopmental and congenital abnormalities ( 103 ). Low USP9X expression is associated with decreased survival in patients with high-risk B-ALL ( 103 ).…”

“…USP9X has been identified as a novel leukemia susceptibility gene associated with B-cell acute lymphoblastic leukemia (B-ALL) and multiple neurodevelopmental and congenital abnormalities ( 103 ). Low USP9X expression is associated with decreased survival in patients with high-risk B-ALL ( 103 ). Genetic or pharmacological inhibition of USP9X can restrict JAK signaling to enhance the survival of cytokine receptor-like factor 2-positive B-ALL in patients with Down syndrome ( 104 ), which suggests that USP9X may exert differential effects in different types of leukemia.…”