DETERMINING THE MUTATIONAL LANDSCAPE OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA REVEALS NR3C1 DELETIONS AND ACTIVATING MUTATIONS IN IL7R SIGNALING AS CAUSE OF STEROID RESISTANCE
(Abstract release date: 05/19/16)
EHA Library. Meijerink J. 06/10/16; 133147; P159
Dr. Jules Meijerink
Contributions
Contributions
Abstract
Abstract: P159
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Response to therapy in children with acute lymphoblastic leukemia (ALL) including in vitro or in vivo steroid response is a strong predictor for survival and cure. T-ALL patients in particular have a high risk to relapse and are refractory to further treatment due to acquired therapy resistance. The mechanisms that underlie steroid resistance are poorly understood.
Aims
This study aimed to investigate the mutational landscape of pediatric T-ALL patients to identify molecular disease mechanisms underlying steroid resistance.
Methods
Whole-genome sequencing (WGS) of 13 T-ALL diagnostic tumor-remission pairs in the pilot group was performed by Complete Genomics to detect chromosomal rearrangements and somatic nucleotide variations. Targeted exome resequencing of 251 genes was performed in a validation cohort of 82 pediatric T-ALL samples, and mutation data was integrated with loss-of-heterozygosity data as obtained by array-comparative genomic hybridization for 53 T-ALL cases. Integrated data was related to clinical outcome and in vitro drug responses.
Results
WGS revealed intra-chromosomal (range of 5-25 per patient) and inter-chromosomal (range of 2-11) breakpoint junctions as consequence of deletions, duplications, inversions, translocations or complex rearrangements. Integrated mutation and copy-number data revealed 151 mutated genes (range of 0-51). Deletions in NR3C1—which are common in 5q chromosomal deletions in patients with the ALL subtype ETP-ALL (early thymus progenitor ALL)—are associated with steroid resistance. Moreover, we found that mutations in interleukin-7 receptor (IL7R) signaling molecules associated with steroid resistance while leaving cellular sensitivity levels to other chemotherapeutics unchanged. IL7R signaling mutations do not impair NR3C1 function, but activate MEK-ERK and PI3K-AKT pathways and downstream anti-apoptotic proteins BCL-XL and MCL1 while inhibiting GSK3B, a key regulator of steroid-induced pro-apoptotic BIM. Importantly, inhibitors of IL7R signaling reversed steroid resistance in T-ALL cells in vitro, whereas a GSK3B inhibitor conferred steroid resistance.
Conclusion
We revealed the mutational landscape of pediatric T-ALL patients. NR3C1 deletions and IL7R signaling mutations were identified as cause for steroid resistance. This study supports the recommendation for the clinical application of IL7R signaling inhibitors to restore—or improve—steroid sensitivity of T-ALL cells.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Prednisolone, T cell acute lymphoblastic leukemia
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Response to therapy in children with acute lymphoblastic leukemia (ALL) including in vitro or in vivo steroid response is a strong predictor for survival and cure. T-ALL patients in particular have a high risk to relapse and are refractory to further treatment due to acquired therapy resistance. The mechanisms that underlie steroid resistance are poorly understood.
Aims
This study aimed to investigate the mutational landscape of pediatric T-ALL patients to identify molecular disease mechanisms underlying steroid resistance.
Methods
Whole-genome sequencing (WGS) of 13 T-ALL diagnostic tumor-remission pairs in the pilot group was performed by Complete Genomics to detect chromosomal rearrangements and somatic nucleotide variations. Targeted exome resequencing of 251 genes was performed in a validation cohort of 82 pediatric T-ALL samples, and mutation data was integrated with loss-of-heterozygosity data as obtained by array-comparative genomic hybridization for 53 T-ALL cases. Integrated data was related to clinical outcome and in vitro drug responses.
Results
WGS revealed intra-chromosomal (range of 5-25 per patient) and inter-chromosomal (range of 2-11) breakpoint junctions as consequence of deletions, duplications, inversions, translocations or complex rearrangements. Integrated mutation and copy-number data revealed 151 mutated genes (range of 0-51). Deletions in NR3C1—which are common in 5q chromosomal deletions in patients with the ALL subtype ETP-ALL (early thymus progenitor ALL)—are associated with steroid resistance. Moreover, we found that mutations in interleukin-7 receptor (IL7R) signaling molecules associated with steroid resistance while leaving cellular sensitivity levels to other chemotherapeutics unchanged. IL7R signaling mutations do not impair NR3C1 function, but activate MEK-ERK and PI3K-AKT pathways and downstream anti-apoptotic proteins BCL-XL and MCL1 while inhibiting GSK3B, a key regulator of steroid-induced pro-apoptotic BIM. Importantly, inhibitors of IL7R signaling reversed steroid resistance in T-ALL cells in vitro, whereas a GSK3B inhibitor conferred steroid resistance.
Conclusion
We revealed the mutational landscape of pediatric T-ALL patients. NR3C1 deletions and IL7R signaling mutations were identified as cause for steroid resistance. This study supports the recommendation for the clinical application of IL7R signaling inhibitors to restore—or improve—steroid sensitivity of T-ALL cells.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Prednisolone, T cell acute lymphoblastic leukemia
Abstract: P159
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Response to therapy in children with acute lymphoblastic leukemia (ALL) including in vitro or in vivo steroid response is a strong predictor for survival and cure. T-ALL patients in particular have a high risk to relapse and are refractory to further treatment due to acquired therapy resistance. The mechanisms that underlie steroid resistance are poorly understood.
Aims
This study aimed to investigate the mutational landscape of pediatric T-ALL patients to identify molecular disease mechanisms underlying steroid resistance.
Methods
Whole-genome sequencing (WGS) of 13 T-ALL diagnostic tumor-remission pairs in the pilot group was performed by Complete Genomics to detect chromosomal rearrangements and somatic nucleotide variations. Targeted exome resequencing of 251 genes was performed in a validation cohort of 82 pediatric T-ALL samples, and mutation data was integrated with loss-of-heterozygosity data as obtained by array-comparative genomic hybridization for 53 T-ALL cases. Integrated data was related to clinical outcome and in vitro drug responses.
Results
WGS revealed intra-chromosomal (range of 5-25 per patient) and inter-chromosomal (range of 2-11) breakpoint junctions as consequence of deletions, duplications, inversions, translocations or complex rearrangements. Integrated mutation and copy-number data revealed 151 mutated genes (range of 0-51). Deletions in NR3C1—which are common in 5q chromosomal deletions in patients with the ALL subtype ETP-ALL (early thymus progenitor ALL)—are associated with steroid resistance. Moreover, we found that mutations in interleukin-7 receptor (IL7R) signaling molecules associated with steroid resistance while leaving cellular sensitivity levels to other chemotherapeutics unchanged. IL7R signaling mutations do not impair NR3C1 function, but activate MEK-ERK and PI3K-AKT pathways and downstream anti-apoptotic proteins BCL-XL and MCL1 while inhibiting GSK3B, a key regulator of steroid-induced pro-apoptotic BIM. Importantly, inhibitors of IL7R signaling reversed steroid resistance in T-ALL cells in vitro, whereas a GSK3B inhibitor conferred steroid resistance.
Conclusion
We revealed the mutational landscape of pediatric T-ALL patients. NR3C1 deletions and IL7R signaling mutations were identified as cause for steroid resistance. This study supports the recommendation for the clinical application of IL7R signaling inhibitors to restore—or improve—steroid sensitivity of T-ALL cells.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Prednisolone, T cell acute lymphoblastic leukemia
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Response to therapy in children with acute lymphoblastic leukemia (ALL) including in vitro or in vivo steroid response is a strong predictor for survival and cure. T-ALL patients in particular have a high risk to relapse and are refractory to further treatment due to acquired therapy resistance. The mechanisms that underlie steroid resistance are poorly understood.
Aims
This study aimed to investigate the mutational landscape of pediatric T-ALL patients to identify molecular disease mechanisms underlying steroid resistance.
Methods
Whole-genome sequencing (WGS) of 13 T-ALL diagnostic tumor-remission pairs in the pilot group was performed by Complete Genomics to detect chromosomal rearrangements and somatic nucleotide variations. Targeted exome resequencing of 251 genes was performed in a validation cohort of 82 pediatric T-ALL samples, and mutation data was integrated with loss-of-heterozygosity data as obtained by array-comparative genomic hybridization for 53 T-ALL cases. Integrated data was related to clinical outcome and in vitro drug responses.
Results
WGS revealed intra-chromosomal (range of 5-25 per patient) and inter-chromosomal (range of 2-11) breakpoint junctions as consequence of deletions, duplications, inversions, translocations or complex rearrangements. Integrated mutation and copy-number data revealed 151 mutated genes (range of 0-51). Deletions in NR3C1—which are common in 5q chromosomal deletions in patients with the ALL subtype ETP-ALL (early thymus progenitor ALL)—are associated with steroid resistance. Moreover, we found that mutations in interleukin-7 receptor (IL7R) signaling molecules associated with steroid resistance while leaving cellular sensitivity levels to other chemotherapeutics unchanged. IL7R signaling mutations do not impair NR3C1 function, but activate MEK-ERK and PI3K-AKT pathways and downstream anti-apoptotic proteins BCL-XL and MCL1 while inhibiting GSK3B, a key regulator of steroid-induced pro-apoptotic BIM. Importantly, inhibitors of IL7R signaling reversed steroid resistance in T-ALL cells in vitro, whereas a GSK3B inhibitor conferred steroid resistance.
Conclusion
We revealed the mutational landscape of pediatric T-ALL patients. NR3C1 deletions and IL7R signaling mutations were identified as cause for steroid resistance. This study supports the recommendation for the clinical application of IL7R signaling inhibitors to restore—or improve—steroid sensitivity of T-ALL cells.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Prednisolone, T cell acute lymphoblastic leukemia
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