THE LANDSCAPE OF SOMATIC ALTERATIONS IN ADULT T-CELL LEUKEMIA/LYMPHOMA
(Abstract release date: 05/21/15)
EHA Library. Kataoka K. 06/13/15; 103057; S456
Disclosure(s): Kyoto University
Dr. Keisuke Kataoka
Contributions
Contributions
Abstract
Abstract: S456
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room Lehar 3 + 4
Background
Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive peripheral T-cell malignancies, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Although HTLV-1 can effectively immortalize infected T cells, there is a long latency period of 30~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional genetic lesions that accumulate during the later life are essential. However, such somatic alterations underlying the pathogenesis of ATL remain elusive.
Aims
The aim of this study is to elucidate the landscape of genetic alterations in ATL.
Methods
We performed an integrated molecular study, in which whole-genome/exome and transcriptome sequencing were performed together with array-based methylation and genomic copy number analysis among a cohort of 81 paired ATL samples, followed by extensive validation using targeted capture sequencing of detected mutations in 370 follow-up samples.
Results
Compared with other hematologic malignancies, ATL cells harbored higher numbers of sequence mutations, copy number alterations, and structural variants, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53, FAS, and CCR4) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, CD58, STAT3 and RHOA), we identified a variety of recurrent mutations affecting previously unknown mutational targets, many of which are involved in development, activation and migration of T-cells, immune surveillance, transcriptional regulation, and histone modification. Molecular and functional analysis using human cell lines showed that some of these novel mutations actually enhance T-cell function, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed several subtype-specific mutations, including TP53 and IRF4 mutations in acute and lymphoma types, and STAT3 mutation in chronic and smoldering types, suggesting that there is a difference in the underlying oncogenic mechanisms between indolent and aggressive forms. Moreover, several mutations, including those in TP53, IRF4 and CCR4, independently predicted worse clinical outcomes. ATL cells showed a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Intriguingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to characterize ATL genomes, although their gene targets remained to be identified. Conspicuously, pathway analysis demonstrated that multiple genes involved in the Tax interactome were systematically altered in ATL, although Tax itself underwent gene silencing in most cases. These data suggested that ATL cells can escape from immune surveillance by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway.
Summary
Our findings suggest that the deregulation of T-cell functionalities caused by genetic alterations, especially those related with HTLV-1 Tax oncoprotein, are pivotal to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics to combat this intractable disease.
Keyword(s): ATL, HTLV-1, Mutation analysis
Session topic: Oncogenic mechanisms and novel targets in non-Hodgkin's lymphoma
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room Lehar 3 + 4
Background
Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive peripheral T-cell malignancies, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Although HTLV-1 can effectively immortalize infected T cells, there is a long latency period of 30~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional genetic lesions that accumulate during the later life are essential. However, such somatic alterations underlying the pathogenesis of ATL remain elusive.
Aims
The aim of this study is to elucidate the landscape of genetic alterations in ATL.
Methods
We performed an integrated molecular study, in which whole-genome/exome and transcriptome sequencing were performed together with array-based methylation and genomic copy number analysis among a cohort of 81 paired ATL samples, followed by extensive validation using targeted capture sequencing of detected mutations in 370 follow-up samples.
Results
Compared with other hematologic malignancies, ATL cells harbored higher numbers of sequence mutations, copy number alterations, and structural variants, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53, FAS, and CCR4) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, CD58, STAT3 and RHOA), we identified a variety of recurrent mutations affecting previously unknown mutational targets, many of which are involved in development, activation and migration of T-cells, immune surveillance, transcriptional regulation, and histone modification. Molecular and functional analysis using human cell lines showed that some of these novel mutations actually enhance T-cell function, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed several subtype-specific mutations, including TP53 and IRF4 mutations in acute and lymphoma types, and STAT3 mutation in chronic and smoldering types, suggesting that there is a difference in the underlying oncogenic mechanisms between indolent and aggressive forms. Moreover, several mutations, including those in TP53, IRF4 and CCR4, independently predicted worse clinical outcomes. ATL cells showed a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Intriguingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to characterize ATL genomes, although their gene targets remained to be identified. Conspicuously, pathway analysis demonstrated that multiple genes involved in the Tax interactome were systematically altered in ATL, although Tax itself underwent gene silencing in most cases. These data suggested that ATL cells can escape from immune surveillance by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway.
Summary
Our findings suggest that the deregulation of T-cell functionalities caused by genetic alterations, especially those related with HTLV-1 Tax oncoprotein, are pivotal to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics to combat this intractable disease.
Keyword(s): ATL, HTLV-1, Mutation analysis
Session topic: Oncogenic mechanisms and novel targets in non-Hodgkin's lymphoma
Abstract: S456
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room Lehar 3 + 4
Background
Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive peripheral T-cell malignancies, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Although HTLV-1 can effectively immortalize infected T cells, there is a long latency period of 30~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional genetic lesions that accumulate during the later life are essential. However, such somatic alterations underlying the pathogenesis of ATL remain elusive.
Aims
The aim of this study is to elucidate the landscape of genetic alterations in ATL.
Methods
We performed an integrated molecular study, in which whole-genome/exome and transcriptome sequencing were performed together with array-based methylation and genomic copy number analysis among a cohort of 81 paired ATL samples, followed by extensive validation using targeted capture sequencing of detected mutations in 370 follow-up samples.
Results
Compared with other hematologic malignancies, ATL cells harbored higher numbers of sequence mutations, copy number alterations, and structural variants, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53, FAS, and CCR4) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, CD58, STAT3 and RHOA), we identified a variety of recurrent mutations affecting previously unknown mutational targets, many of which are involved in development, activation and migration of T-cells, immune surveillance, transcriptional regulation, and histone modification. Molecular and functional analysis using human cell lines showed that some of these novel mutations actually enhance T-cell function, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed several subtype-specific mutations, including TP53 and IRF4 mutations in acute and lymphoma types, and STAT3 mutation in chronic and smoldering types, suggesting that there is a difference in the underlying oncogenic mechanisms between indolent and aggressive forms. Moreover, several mutations, including those in TP53, IRF4 and CCR4, independently predicted worse clinical outcomes. ATL cells showed a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Intriguingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to characterize ATL genomes, although their gene targets remained to be identified. Conspicuously, pathway analysis demonstrated that multiple genes involved in the Tax interactome were systematically altered in ATL, although Tax itself underwent gene silencing in most cases. These data suggested that ATL cells can escape from immune surveillance by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway.
Summary
Our findings suggest that the deregulation of T-cell functionalities caused by genetic alterations, especially those related with HTLV-1 Tax oncoprotein, are pivotal to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics to combat this intractable disease.
Keyword(s): ATL, HTLV-1, Mutation analysis
Session topic: Oncogenic mechanisms and novel targets in non-Hodgkin's lymphoma
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room Lehar 3 + 4
Background
Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive peripheral T-cell malignancies, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Although HTLV-1 can effectively immortalize infected T cells, there is a long latency period of 30~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional genetic lesions that accumulate during the later life are essential. However, such somatic alterations underlying the pathogenesis of ATL remain elusive.
Aims
The aim of this study is to elucidate the landscape of genetic alterations in ATL.
Methods
We performed an integrated molecular study, in which whole-genome/exome and transcriptome sequencing were performed together with array-based methylation and genomic copy number analysis among a cohort of 81 paired ATL samples, followed by extensive validation using targeted capture sequencing of detected mutations in 370 follow-up samples.
Results
Compared with other hematologic malignancies, ATL cells harbored higher numbers of sequence mutations, copy number alterations, and structural variants, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53, FAS, and CCR4) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, CD58, STAT3 and RHOA), we identified a variety of recurrent mutations affecting previously unknown mutational targets, many of which are involved in development, activation and migration of T-cells, immune surveillance, transcriptional regulation, and histone modification. Molecular and functional analysis using human cell lines showed that some of these novel mutations actually enhance T-cell function, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed several subtype-specific mutations, including TP53 and IRF4 mutations in acute and lymphoma types, and STAT3 mutation in chronic and smoldering types, suggesting that there is a difference in the underlying oncogenic mechanisms between indolent and aggressive forms. Moreover, several mutations, including those in TP53, IRF4 and CCR4, independently predicted worse clinical outcomes. ATL cells showed a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Intriguingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to characterize ATL genomes, although their gene targets remained to be identified. Conspicuously, pathway analysis demonstrated that multiple genes involved in the Tax interactome were systematically altered in ATL, although Tax itself underwent gene silencing in most cases. These data suggested that ATL cells can escape from immune surveillance by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway.
Summary
Our findings suggest that the deregulation of T-cell functionalities caused by genetic alterations, especially those related with HTLV-1 Tax oncoprotein, are pivotal to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics to combat this intractable disease.
Keyword(s): ATL, HTLV-1, Mutation analysis
Session topic: Oncogenic mechanisms and novel targets in non-Hodgkin's lymphoma
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