A new sUSPect in T-ALL risk stratification Open Access

In this issue of Blood Advances, Illarregi et al¹ identify USP7 single-nucleotide variants (SNVs) as a potential prognostic marker for patients with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of relapse. This retrospective, single-center study included 9 pediatric patients with newly diagnosed T-ALL, aged 4 to 14 years, who were treated under the SEHOP-PETHEMA 2013 protocol. Using RNA sequencing, it was determined that 3 of 9 patients had alterations in the USP7 gene, 2 of whom had an event during follow-up as compared with 1 of 6 patients without USP7 alterations. The authors also evaluated recently published genomic data from the Children’s Oncology Group (COG) AALL0434 trial and found that patients aged <15 years with USP7 SNVs had statistically significant inferior event-free survival (EFS) and disease-free survival (DFS) (5-year EFS: 73.5% vs 82.9%; P = .045 and 5-year DFS: 71% vs 84.9%; P = .007). In multivariate analysis that included traditional prognostic variables for T-ALL, such as end-of-induction measurable residual disease (EOI MRD) and central nervous system (CNS) status, USP7 SNVs retained prognostic significance as an independent predictor of inferior EFS/DFS.

Relapsed T-ALL portends a poor prognosis with salvage rates of <25%, highlighting the importance of prognostic marker identification at diagnosis to improve outcomes for high-risk patients.² Whereas risk stratification for B-cell ALL is highly refined,^3,4 few biomarkers have been identified in T-ALL that are reproducibly prognostic independent of treatment response. Nevertheless, recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with independent prognostic value.⁵ For example, Pölönen et al identified up to 15 distinct molecular subtypes of T-ALL, each characterized by unique genomic drivers, gene expression, and developmental arrest stages, and impact on outcomes, including treatment response and survival. Despite these discoveries, there remains no independent validation of risk stratification models that incorporate both clinical and genomic information across different cohorts of patients.

In this study, USP7 is proposed as a potential new marker for poor prognosis. Biologically, USP7 encodes a deubiquitinase that directly regulates protein stability of NOTCH1, a pivotal driver in T-ALL development and progression. Alterations in USP7 may disrupt NOTCH1 degradation, resulting in sustained NOTCH1 signaling and promoting leukemogenesis.⁶ Interestingly, recent work by Gocho et al established that ∼40% of childhood T-ALL cases are predicted to be sensitive to treatment with dasatinib based on pre–T-cell receptor–lymphocyte-specific protein tyrosine kinase activation, a pathway that USP7 was recently shown to potentially activate.⁷ 

Using a large validation cohort from COG, a major strength of this study is the proposed integrated risk stratification model using USP7 SNVs with known prognostic variables. Very high–risk patients included those with USP7 SNVs, positive EOI MRD, and/or CNS3 disease (n = 29/1078; 5-year EFS 52.3%; DFS: 62%), high risk patients included those with either positive EOI MRD or USP7 SNVs (n = 424/1078; 5-year EFS 76.3%; DFS: 79.4%), and/or CNS3 disease, and intermediate risk patients included those without any of the aforementioned poor prognostic markers (n = 625/1078; 5-year EFS: 87.8%; DFS 88.5%; P < .001 for both EFS and DFS). Additional studies are needed to determine if USP7 SNVs can be integrated into other recently published T-ALL risk-stratification models.^5,8-12 As an example, Simonin et al recently published a 12-gene next-generation sequencing gene risk-stratification model for patients with T-ALL,^13,14 and Schäfer Hackenhaar et al recently published a methylation-based risk classifier for patients with T-ALL. Further, Newman et al recently found that the prognostic significance of some genes in T-ALL varied based on germline genetic ancestry. Prior studies demonstrated USP7 germline variants were enriched in patients of African descent, but it is unknown if USP7 alterations have differential prognostic significance in different ancestral populations.^15,16 

Several limitations of this study include the low frequency of USP7 SNVs (∼4%), the inability of USP7 to retain prognostic significance in the AALL0434 cohort when patients aged 15 to 30 years were included in the analyses, and the lack of another large independent cohort to confirm the prognostic significance of USP7. In addition, it is unknown if USP7 alterations will retain independent prognostic significance if at a later timepoint MRD (such as end of consolidation) is included in modeling. The mechanistic link between USP7 alteration and its downstream effects in T-ALL will need to be better understood to tailor therapeutic options. As with other potential genetic classifiers, integration into prospective risk-stratified protocols will be needed to ascertain true clinical utility.

Conflict-of-interest disclosure: The authors declare no competing financial interests.