IL7R OVEREXPRESSION IN ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): PROGNOSTIC IMPLICATIONS IN B-LINEAGE ALL WITHOUT RECURRENT FUSION TRANSCRIPTS
(Abstract release date: 05/19/16)
EHA Library. Gianfelici V. 06/09/16; 132401; E852
Dr. Valentina Gianfelici
Contributions
Contributions
Abstract
Abstract: E852
Type: Eposter Presentation
Background
The IL7 receptor alpha chain (IL7R) heterodimerizes either with the IL2RG to form the IL7 receptor or with CRLF2 to form the receptor for the thymic stromal lymphopoietin (TSLP) both in T and B-cells. Signaling from these receptors activates the JAK/STAT pathway that is frequently altered both in T- and B-lineage acute lymphoblastic leukemia (ALL), due to mutations of its members. Among them, IL7R mutations are relatively common in adult B-ALL without recurrent transcripts (B-NEG) and in T-ALL. In a cohort of adult ALL previously studied by gene expression profiling (GEP) we observed that IL7R expression levels were variable, with a considerable number of B-NEG and T-ALL cases overexpressing it, thus suggesting that its deregulation may rely on different mechanisms.
Aims
To evaluate the clinical relevance of IL7R expression levels in adult B-NEG and T-ALL, we correlated the levels of IL7R expression with patients’ outcome and analyzed the transcription profile of IL7R-high cases.
Methods
IL7R expression levels were inferred from previously performed GEP studies (Affymetrix) of adult ALL, including 78 B-NEG and 68 T-ALL. Martingale residual analysis was used to select the optimal IL7R cut-off, which was computed separately for these two groups. Differences in survival curves of IL7R-high and IL7R-low were calculated by the log-rank test. GEP of IL7R-high was analyzed and correlated with the molecular and immunophenotypic features. Screening of the JAK/STAT genes recurrently mutated was performed by Sanger in 66/78 B-NEG (IL7R, CRLF2, JAK2) and 38/68 T-ALL (IL7R, JAK1/3, STAT5B).
Results
IL7R expression levels were extremely heterogeneous both in B-NEG (mean 656.9, range 43.8-3000) and in T-ALL (mean 1047 range 58.9-5874). Martingale residual analysis provided a cut-off of 500 for B-NEG and 1000 for T-ALL. By using these cut-points, 47% of B-NEG and 41% of T-ALL cases were defined as IL7R-high.In B-NEG, correlation between IL7R expression levels and outcome showed that IL7R-high cases had a significantly shorter OS at 4 years than IL7R-low (31% vs 62%, p=0.04). Similarly, in T-ALL a trend towards a poorer OS was observed in IL7R-high patients than IL7R-low (27% vs 40%, p=0.2).The comparison of IL7R-high and IL7R-low by supervised GEP analysis identified a set of differentially expressed genes both in B-NEG (157 genes) and T-ALL (208 genes); only 11 transcripts overlapped. Indeed, functional annotation analysis of upregulated genes in IL7R-high highlighted an enrichment of JAK/STAT, Wnt and ErbB signaling members in B-NEG cases and of JAK/STAT and Notch pathway members in T-ALL, suggesting the involvement of different downstream cascades.As per the associations with other biological features, IL7R levels were significantly lower in TAL1 cluster than in other subgroups (p=0.005). Notably, we observed a significant association between IL7R high expression and JAK/STAT pathway mutations both in B-NEG and T-ALL (p=0.001 and 0.03, respectively), thus indicating that IL7R-high might be a marker of an underlying JAK/STAT mutation.
Conclusion
Overall, our findings indicate that IL7R altered expression may represent a novel prognostic marker in B-NEG cases and, to a lesser extent, in T-ALL. Given the different GEP observed between IL7R-high B-NEG and IL7R-high T-ALL, it is intriguing to speculate that IL7R deregulation may activate different pathways. Furthermore, IL7R overexpression should prompt the investigation of JAK/STAT mutations both in B-NEG and T-ALL. However, given the overall incidence of JAK/STAT mutations it is likely that IL7R overexpression might be also sustained by other mechanisms that are currently under investigation.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Adult, Clinical outcome, Gene expression
Type: Eposter Presentation
Background
The IL7 receptor alpha chain (IL7R) heterodimerizes either with the IL2RG to form the IL7 receptor or with CRLF2 to form the receptor for the thymic stromal lymphopoietin (TSLP) both in T and B-cells. Signaling from these receptors activates the JAK/STAT pathway that is frequently altered both in T- and B-lineage acute lymphoblastic leukemia (ALL), due to mutations of its members. Among them, IL7R mutations are relatively common in adult B-ALL without recurrent transcripts (B-NEG) and in T-ALL. In a cohort of adult ALL previously studied by gene expression profiling (GEP) we observed that IL7R expression levels were variable, with a considerable number of B-NEG and T-ALL cases overexpressing it, thus suggesting that its deregulation may rely on different mechanisms.
Aims
To evaluate the clinical relevance of IL7R expression levels in adult B-NEG and T-ALL, we correlated the levels of IL7R expression with patients’ outcome and analyzed the transcription profile of IL7R-high cases.
Methods
IL7R expression levels were inferred from previously performed GEP studies (Affymetrix) of adult ALL, including 78 B-NEG and 68 T-ALL. Martingale residual analysis was used to select the optimal IL7R cut-off, which was computed separately for these two groups. Differences in survival curves of IL7R-high and IL7R-low were calculated by the log-rank test. GEP of IL7R-high was analyzed and correlated with the molecular and immunophenotypic features. Screening of the JAK/STAT genes recurrently mutated was performed by Sanger in 66/78 B-NEG (IL7R, CRLF2, JAK2) and 38/68 T-ALL (IL7R, JAK1/3, STAT5B).
Results
IL7R expression levels were extremely heterogeneous both in B-NEG (mean 656.9, range 43.8-3000) and in T-ALL (mean 1047 range 58.9-5874). Martingale residual analysis provided a cut-off of 500 for B-NEG and 1000 for T-ALL. By using these cut-points, 47% of B-NEG and 41% of T-ALL cases were defined as IL7R-high.In B-NEG, correlation between IL7R expression levels and outcome showed that IL7R-high cases had a significantly shorter OS at 4 years than IL7R-low (31% vs 62%, p=0.04). Similarly, in T-ALL a trend towards a poorer OS was observed in IL7R-high patients than IL7R-low (27% vs 40%, p=0.2).The comparison of IL7R-high and IL7R-low by supervised GEP analysis identified a set of differentially expressed genes both in B-NEG (157 genes) and T-ALL (208 genes); only 11 transcripts overlapped. Indeed, functional annotation analysis of upregulated genes in IL7R-high highlighted an enrichment of JAK/STAT, Wnt and ErbB signaling members in B-NEG cases and of JAK/STAT and Notch pathway members in T-ALL, suggesting the involvement of different downstream cascades.As per the associations with other biological features, IL7R levels were significantly lower in TAL1 cluster than in other subgroups (p=0.005). Notably, we observed a significant association between IL7R high expression and JAK/STAT pathway mutations both in B-NEG and T-ALL (p=0.001 and 0.03, respectively), thus indicating that IL7R-high might be a marker of an underlying JAK/STAT mutation.
Conclusion
Overall, our findings indicate that IL7R altered expression may represent a novel prognostic marker in B-NEG cases and, to a lesser extent, in T-ALL. Given the different GEP observed between IL7R-high B-NEG and IL7R-high T-ALL, it is intriguing to speculate that IL7R deregulation may activate different pathways. Furthermore, IL7R overexpression should prompt the investigation of JAK/STAT mutations both in B-NEG and T-ALL. However, given the overall incidence of JAK/STAT mutations it is likely that IL7R overexpression might be also sustained by other mechanisms that are currently under investigation.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Adult, Clinical outcome, Gene expression
Abstract: E852
Type: Eposter Presentation
Background
The IL7 receptor alpha chain (IL7R) heterodimerizes either with the IL2RG to form the IL7 receptor or with CRLF2 to form the receptor for the thymic stromal lymphopoietin (TSLP) both in T and B-cells. Signaling from these receptors activates the JAK/STAT pathway that is frequently altered both in T- and B-lineage acute lymphoblastic leukemia (ALL), due to mutations of its members. Among them, IL7R mutations are relatively common in adult B-ALL without recurrent transcripts (B-NEG) and in T-ALL. In a cohort of adult ALL previously studied by gene expression profiling (GEP) we observed that IL7R expression levels were variable, with a considerable number of B-NEG and T-ALL cases overexpressing it, thus suggesting that its deregulation may rely on different mechanisms.
Aims
To evaluate the clinical relevance of IL7R expression levels in adult B-NEG and T-ALL, we correlated the levels of IL7R expression with patients’ outcome and analyzed the transcription profile of IL7R-high cases.
Methods
IL7R expression levels were inferred from previously performed GEP studies (Affymetrix) of adult ALL, including 78 B-NEG and 68 T-ALL. Martingale residual analysis was used to select the optimal IL7R cut-off, which was computed separately for these two groups. Differences in survival curves of IL7R-high and IL7R-low were calculated by the log-rank test. GEP of IL7R-high was analyzed and correlated with the molecular and immunophenotypic features. Screening of the JAK/STAT genes recurrently mutated was performed by Sanger in 66/78 B-NEG (IL7R, CRLF2, JAK2) and 38/68 T-ALL (IL7R, JAK1/3, STAT5B).
Results
IL7R expression levels were extremely heterogeneous both in B-NEG (mean 656.9, range 43.8-3000) and in T-ALL (mean 1047 range 58.9-5874). Martingale residual analysis provided a cut-off of 500 for B-NEG and 1000 for T-ALL. By using these cut-points, 47% of B-NEG and 41% of T-ALL cases were defined as IL7R-high.In B-NEG, correlation between IL7R expression levels and outcome showed that IL7R-high cases had a significantly shorter OS at 4 years than IL7R-low (31% vs 62%, p=0.04). Similarly, in T-ALL a trend towards a poorer OS was observed in IL7R-high patients than IL7R-low (27% vs 40%, p=0.2).The comparison of IL7R-high and IL7R-low by supervised GEP analysis identified a set of differentially expressed genes both in B-NEG (157 genes) and T-ALL (208 genes); only 11 transcripts overlapped. Indeed, functional annotation analysis of upregulated genes in IL7R-high highlighted an enrichment of JAK/STAT, Wnt and ErbB signaling members in B-NEG cases and of JAK/STAT and Notch pathway members in T-ALL, suggesting the involvement of different downstream cascades.As per the associations with other biological features, IL7R levels were significantly lower in TAL1 cluster than in other subgroups (p=0.005). Notably, we observed a significant association between IL7R high expression and JAK/STAT pathway mutations both in B-NEG and T-ALL (p=0.001 and 0.03, respectively), thus indicating that IL7R-high might be a marker of an underlying JAK/STAT mutation.
Conclusion
Overall, our findings indicate that IL7R altered expression may represent a novel prognostic marker in B-NEG cases and, to a lesser extent, in T-ALL. Given the different GEP observed between IL7R-high B-NEG and IL7R-high T-ALL, it is intriguing to speculate that IL7R deregulation may activate different pathways. Furthermore, IL7R overexpression should prompt the investigation of JAK/STAT mutations both in B-NEG and T-ALL. However, given the overall incidence of JAK/STAT mutations it is likely that IL7R overexpression might be also sustained by other mechanisms that are currently under investigation.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Adult, Clinical outcome, Gene expression
Type: Eposter Presentation
Background
The IL7 receptor alpha chain (IL7R) heterodimerizes either with the IL2RG to form the IL7 receptor or with CRLF2 to form the receptor for the thymic stromal lymphopoietin (TSLP) both in T and B-cells. Signaling from these receptors activates the JAK/STAT pathway that is frequently altered both in T- and B-lineage acute lymphoblastic leukemia (ALL), due to mutations of its members. Among them, IL7R mutations are relatively common in adult B-ALL without recurrent transcripts (B-NEG) and in T-ALL. In a cohort of adult ALL previously studied by gene expression profiling (GEP) we observed that IL7R expression levels were variable, with a considerable number of B-NEG and T-ALL cases overexpressing it, thus suggesting that its deregulation may rely on different mechanisms.
Aims
To evaluate the clinical relevance of IL7R expression levels in adult B-NEG and T-ALL, we correlated the levels of IL7R expression with patients’ outcome and analyzed the transcription profile of IL7R-high cases.
Methods
IL7R expression levels were inferred from previously performed GEP studies (Affymetrix) of adult ALL, including 78 B-NEG and 68 T-ALL. Martingale residual analysis was used to select the optimal IL7R cut-off, which was computed separately for these two groups. Differences in survival curves of IL7R-high and IL7R-low were calculated by the log-rank test. GEP of IL7R-high was analyzed and correlated with the molecular and immunophenotypic features. Screening of the JAK/STAT genes recurrently mutated was performed by Sanger in 66/78 B-NEG (IL7R, CRLF2, JAK2) and 38/68 T-ALL (IL7R, JAK1/3, STAT5B).
Results
IL7R expression levels were extremely heterogeneous both in B-NEG (mean 656.9, range 43.8-3000) and in T-ALL (mean 1047 range 58.9-5874). Martingale residual analysis provided a cut-off of 500 for B-NEG and 1000 for T-ALL. By using these cut-points, 47% of B-NEG and 41% of T-ALL cases were defined as IL7R-high.In B-NEG, correlation between IL7R expression levels and outcome showed that IL7R-high cases had a significantly shorter OS at 4 years than IL7R-low (31% vs 62%, p=0.04). Similarly, in T-ALL a trend towards a poorer OS was observed in IL7R-high patients than IL7R-low (27% vs 40%, p=0.2).The comparison of IL7R-high and IL7R-low by supervised GEP analysis identified a set of differentially expressed genes both in B-NEG (157 genes) and T-ALL (208 genes); only 11 transcripts overlapped. Indeed, functional annotation analysis of upregulated genes in IL7R-high highlighted an enrichment of JAK/STAT, Wnt and ErbB signaling members in B-NEG cases and of JAK/STAT and Notch pathway members in T-ALL, suggesting the involvement of different downstream cascades.As per the associations with other biological features, IL7R levels were significantly lower in TAL1 cluster than in other subgroups (p=0.005). Notably, we observed a significant association between IL7R high expression and JAK/STAT pathway mutations both in B-NEG and T-ALL (p=0.001 and 0.03, respectively), thus indicating that IL7R-high might be a marker of an underlying JAK/STAT mutation.
Conclusion
Overall, our findings indicate that IL7R altered expression may represent a novel prognostic marker in B-NEG cases and, to a lesser extent, in T-ALL. Given the different GEP observed between IL7R-high B-NEG and IL7R-high T-ALL, it is intriguing to speculate that IL7R deregulation may activate different pathways. Furthermore, IL7R overexpression should prompt the investigation of JAK/STAT mutations both in B-NEG and T-ALL. However, given the overall incidence of JAK/STAT mutations it is likely that IL7R overexpression might be also sustained by other mechanisms that are currently under investigation.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Adult, Clinical outcome, Gene expression
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