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Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia
Marion Alcantara1, Mathieu Simonin1,2,3, Ludovic Lhermitte1
1Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
Abstract:
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).
Insights
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) loss occurs in 8% of T-cell acute lymphoblastic leukemia (T-ALL) cases. PTPN2 deletions correlate with specific genetic alterations and impact treatment response, particularly in pediatric T-ALL.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is recognized as a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL).
- The comprehensive clinicobiologic features associated with PTPN2 loss are not well-documented.
- Understanding PTPN2's role is crucial for refining T-ALL diagnostics and therapeutics.
Purpose of the Study:
- To conduct a detailed analysis of PTPN2 deletions in a large cohort of adult and pediatric T-ALL patients.
- To investigate the clinicobiologic implications of PTPN2 loss, including genetic associations and treatment outcomes.
- To evaluate the relationship between PTPN2 deletions and other genetic alterations within T-ALL.
Main Methods:
- Utilized multiplex ligation-dependent probe amplification (MLPA) to detect PTPN2 deletions.
- Analyzed a cohort of 430 T-ALL patients (216 adults, 214 children) treated under specific clinical protocols (GRAALL03/05, FRALLE2000).
- Correlated PTPN2 deletion status with lineage, gene deregulation, mutational genotype, and treatment response.
Main Results:
- Identified an 8% incidence of PTPN2 deletion across the cohort, with similar rates in adults (9%) and children (6%).
- PTPN2 deletions were significantly associated with αβ lineage and TLX1 deregulation.
- In adult T-ALL, PTPN2 deletions correlated with IL7R/JAK-STAT pathway mutations, PHF6, and WT1 mutations; PTPN2 and PTEN deletions were mutually exclusive.
- PTPN2-deleted T-ALL showed enhanced glucocorticoid response and a trend towards improved survival in children (5-year CIR 8% vs. 26%).
Conclusions:
- PTPN2 deletions are a notable genetic event in T-ALL, occurring across adult and pediatric populations.
- PTPN2 loss is linked to specific molecular subtypes and signaling pathway alterations in T-ALL.
- PTPN2 deletion status may serve as a predictive biomarker for treatment response and prognosis, particularly in pediatric T-ALL.
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