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  • 1
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    Integrated molecular analysis of adult T cell leukemia/lymphoma
    Springer Science and Business Media LLC ; 2015
    In:  Nature Genetics Vol. 47, No. 11 ( 2015-11), p. 1304-1315
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 47, No. 11 ( 2015-11), p. 1304-1315
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/ng.3415
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 2
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    De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome
    Elsevier BV ; 2018
    In:  The American Journal of Human Genetics Vol. 103, No. 3 ( 2018-09), p. 440-447
    Details
    In: The American Journal of Human Genetics, Elsevier BV, Vol. 103, No. 3 ( 2018-09), p. 440-447
    Type of Medium: Online Resource
    ISSN: 0002-9297
    URL: Article
    DOI: 10.1016/j.ajhg.2018.07.020
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 1473813-2
    SSG: 12
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  • 3
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    Comprehensive Analysis of Aberrant RNA Splicing in Myelodysplastic Syndromes
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 826-826
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 826-826
    Abstract: Introduction Splicing factor (SF) mutations represent a novel class of driver mutations highly prevalent in myelodysplastic syndromes (MDS), where four genes, including SF3B1, SRSF2, U2AF1, and ZRSR2, are most frequently affected. SF3B1 and SRSF2 mutations show prominent specificity to RARS/RCMD-RS and CMML subtypes, respectively. Although abnormal RNA splicing is thought to play a central role in the pathogenic mechanism of mutated SFs, little is known about exact gene targets, whose abnormal splicing is implicated in the pathogenesis of MDS or about the molecular mechanism that explains the unique subtype specificity of SF mutations, especially to those subtypes characterized by increased ring sideroblasts. Methods To address these issues, comprehensive analysis of abnormal RNA splicing was performed for a total of 336 MDS patients with different SF mutations. High-quality RNA was extracted from bone marrow mononuclear cells (BM/MNCs) and/or CD34+ cells and subjected to high-throughput sequencing, followed by exhaustive detection of splicing junctions for all relevant reads. Aberrant splicing events associated with different SF mutations were explored by comparing observed splicing junctions between samples with and without mutations. To specifically determine the role of SF3B1 mutations in ring sideroblast formation, CD34+ bone marrow cells from 13 patients with or without SF3B1 mutations were differentiated in vitro into erythroid cells. RNA sequencing was performed on cells recovered on day 7 and day 14 and differentially spliced genes in erythroid cells between SF3B1-mutated and unmutated samples were investigated. Results SF3B1, SRSF2, U2AF1, and ZRSR2 were mutated in 28%, 18%, 5%, and 7% of the patients, respectively. First, we compared SF3B1-mutated samples with those without known SF mutations. RNA sequencing of CD34+ cells revealed 230 splicing events significantly enriched in SF3B1-mutated cases, of which 90% (n = 206) were caused by misrecognition of 3' splice sites. A similar result was obtained in the experiment for BM/MNCs, where 177 (83%) out of 206 splicing events significantly enriched in SF3B1-mutated samples were caused by misrecognition of 3' splice sites. These observations were in accordance with the known function of SF3B1 in branch point recognition in the U2 snRNP complex. In both BM/MNCs and CD34+ cells, approximately 70% of the unusual 3' splice sites were located from 5 to 25 bases downstream from the authentic junctions. The bases immediately upstream to these 3' splice sites were more often pyrimidines, which was not accordance with the general rule: the bases next to 3' splice sites are purines, especially guanines. About 50% of these altered 3' splice sites resulted in frameshift, indicating that SF3B1 mutations cause deleterious effects in many genes simultaneously. Next, to explore the genes whose abnormal splicing is responsible for increased ring sideroblast formation, RNA sequencing was carried out for erythroid progenitor cells differentiated in vitro from CD34+ cells from MDS patients with or without SF3B1 mutations. We found that a total of 146 altered 3' splice sites were significantly associated with SF3B1 mutations, of which 87 were overlapped to the aberrant splice sites shown to be enriched in SF3B1 mutated primary MDS specimens. These splice sites were found in genes involved in heme biosynthesis, cell cycle progression, and DNA repair and their consequence was mostly deleterious due to aberrant frameshifts. Abnormal splicing events associated with other SF mutations were also identified. Among these, the most common abnormalities associated with mutated SRSF2 and U2AF1 were alternative exon usage. Misrecognition of 3' splice sites was also common in U2AF1-mutated cases. ZRSR2 mutations were associated with retentions of U12 introns, which is consistent with the known role of ZRSR2 as an essential component of the minor (U12-type) spliceosome. Conclusion SF mutations were associated with characteristic abnormal splicing changes in primary MDS samples as well as in vitro cultured cells. Our results provide insights into the pathogenic role of SF mutations in MDS. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.826.826
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    Landscape of Genetic Alterations in Adult T-Cell Leukemia/Lymphoma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 75-75
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 75-75
    Abstract: Adult T-cell leukemia/lymphoma (ATL) is a distinct form of peripheral T-cell lymphoma, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection during early infancy. Although HTLV-1 can effectively immortalize human T cells, there is a long latency period of ~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional acquired genetic events that accumulate during the later life are essential for the development of ATL. However, such somatic alterations underlying the pathogenesis of ATL have not been fully elucidated. To obtain a complete registry of genetic alterations in ATL, we performed an integrated genetic study, in which whole-genome/exome and RNA sequencing (RNA-seq) was performed together with array-based methylation and genomic copy number analysis among a cohort of 50 paired ATL samples, followed by extensive validation using targeted deep sequencing of detected mutations in 〉 400 follow-up samples. Compared with other lymphoid malignancies, ATL cells carried higher numbers of mutations, copy number alterations, and rearrangements than in other lymphoid malignancies, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53,TCF8, and FAS) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, and RHOA), we identified a variety of highly recurrent mutations affecting previously unknown mutational targets, many of which are involved in T-cell development, activation and migration, immunosurveillance, and transcriptional regulation. Molecular and functional analysis using human T-cell leukemia cell lines showed that some of these novel mutations actually augment T-cell receptor signaling, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed that several subtype-specific mutations, including TP53, CD58, IRF4 and TBL1XR1 mutations in acute and lymphoma types, and STAT3mutation in chronic and smoldering types, suggesting that different oncogenic mechanisms underlie different ATL subtypes. Furthermore, ATL cells had a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Surprisingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to uniquely characterize ATL genomes, although their gene targets remained to be identified. Like other regions also frequently deleted in ATL, such as 7q31.1 and 1p21.3 loci, these deletions were thought to reflect high levels of genetic instability. Finally and conspicuously, pathway analysis revealed 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 cytotoxic T-lymphocytes by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway. Our findings suggest that deregulated T-cell functionalities caused by genetic alterations, especially those associated with HTLV-1 Tax oncoprotein, are central to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics for this intractable disease. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.75.75
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Variegated RHOA mutations in adult T-cell leukemia/lymphoma
    American Society of Hematology ; 2016
    In:  Blood Vol. 127, No. 5 ( 2016-02-04), p. 596-604
    Details
    In: Blood, American Society of Hematology, Vol. 127, No. 5 ( 2016-02-04), p. 596-604
    Abstract: RHOA mutations are common in ATLL and show a unique distribution compared with other T-cell lymphomas. Depending on patients, functionally distinct RHOA mutations are clonally selected and involved in the pathogenesis of ATLL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2015-06-644948
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Mutational landscape and clonal architecture in grade II and III gliomas
    Springer Science and Business Media LLC ; 2015
    In:  Nature Genetics Vol. 47, No. 5 ( 2015-5), p. 458-468
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 47, No. 5 ( 2015-5), p. 458-468
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/ng.3273
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 1494946-5
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  • 7
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    Chronological Analysis of Clonal Evolution in Acquired Aplastic Anemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 253-253
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 253-253
    Abstract: Background: Acquired aplastic anemia (AA), the prototypical bone marrow failure syndrome, is inferred to result from immune-mediated destruction of hematopoietic progenitors, as most patients respond to immunosuppressive therapies. Clonal hematopoiesis in AA is evident in the presence of paroxysmal nocturnal hemoglobinuria (PNH) cells in as many as half of patients and by identification of uniparental disomies involving 6p (6pUPD) chromosome in 13% of cases. In addition, "clonal transformation", as defined by the development of myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) is a serious long-term complication in 10-15% AA patients. Methods: We performed targeted deep sequencing and SNP array-based copy number (CN) analysis of peripheral blood- or granulocyte-derived DNA from 439 patients with AA (280 from US and 159 from Japanese cohorts) for a panel of 103 candidate genes, chosen because they are known to be frequently mutated in myeloid neoplasms. Germline DNA was available for 288 out of 439 patients and was used to confirm the somatic origin of mutations. Whole exome sequencing (WES) was performed in 52 cases. Where serial samples were available, the chronology of detected mutations was also investigated. Results: Targeted deep sequencing provided highly concordant results between the US and Japanese cohorts; approximately one third of AA patients had mutations in genes commonly affected in myeloid neoplasms, and about one third of patients in whom mutations were identified had multiple mutations. Multi-lineage involvement of mutations was confirmed in 6 cases using flow-sorted bone marrow samples. However, compared to myeloid neoplasms, mutations in AA were at much lower variant allele frequencies (VAFs) ( 〈 10% on average) and most frequently involved 5 genes: PIGA, BCOR/BCORL1, DNMT3A and ASXL1 (Fig.1). Although CN abnormalities were rare, about 13% of AA patients in both cohorts showed 6pUPD. Combined, clonal hematopoiesis was detected in as many as 46.5% and 47.8% of US and Japanese patients, respectively. We focused efforts on the large NIH cohort, due to accessible serial samples and well characterized clinical phenotypes at many time points. For 46 cases for which diagnostic samples were available, mutations were detected from at the time of diagnosis but at very low VAFs. The size of DNMT3A or ASXL1 mutated clones tended to increase over time, regardless of the emergence of chromosomal anomalies or blasts, whereas that of BCOR or PIGA mutated clones was more likely to decrease or remain stable. In both patient cohorts, presence of an acquired mutation was associated with older age, but did not correlate with response to immunosuppressive therapy (IST) or overall survival (OS). Mutations in PIGA and BCOR/BCORL1 were more common in AA than in MDS/AML and when combined, were associated with favorable OS (favorable mutations) (P = 0.044). Conversely, 17 high-risk mutations were extracted to predict poor OS (Fig. 2), which combined with favorable mutations, could be used to stratify AA patients with regard to OS (P = 0.0025). WES allowed capture of more mutations and better characterization of clonal hematopoiesis: more than 60% of AA patients had somatic mutations by combined targeted and whole exome sequencing. In 36 cases, WES was performed for all available serial samples, which enabled comprehensive monitoring of the dynamic chronological behavior of hematopoietic clones for as long as a decade after diagnosis. In many cases, clonal hematopoiesis developed gradually and was unrelated to the severity of cytopenias or to clinical evolution to abnormal cytogenetics, marrow dysplasia, and leukemia. Acquisition of new mutations within founder clones and subsequent selection shaped highly complex clonal structures in some cases (Fig. 3). The emergence of clonal hematopoiesis predated the development of MDS or leukemic transformation, with clones often detectable at time of diagnosis. Conclusions: Clonal hematopoiesis in AA was prevalent, associated in about half of cases with mutations in genes recurrently mutated in myeloid neoplasms. The highly biased set of mutated genes associated with clonal hematopoiesis in AA is evidence for Darwinian selection of particular cell clones under in the bone marrow failure environment. Mutations could be used to better predict prognosis of AA patients. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.253.253
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Frequent Activating Somatic Alterations in T-Cell Receptor / NF-κb Signaling in Adult T-Cell Leukemia/Lymphoma
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 113-113
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 113-113
    Abstract: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm of largely unknown genetic basis, which is associated with human T-cell leukemia virus type-1 (HTLV-1) infection. To delineate a genetic landscape of somatic alterations in ATL, we have performed an integrated genetic study, in which whole-genome/exome (WGS/WES) and transcriptome sequencing (RNA-seq) was performed for a cohort of 83 paired ATL samples, followed by extensive validation using targeted sequencing of detected mutations in 370 follow-up samples. A striking feature of driver lesions in ATL was their strong enrichment in the components of T-cell receptor (TCR) / NF-κB pathway. Accounting for more than 90% of ATL cases, these lesions were characterized by the predominance of activating alterations, including hotspot missense mutations in PLCG1 (36%), PRKCB (33%), CARD11 (24%), VAV1 (18%), IRF4 (14%) and FYN (4%). Among these, most frequently mutated was PLCG1, which encodes phospholipase C γ1 (PLCγ1), a key regulator of the proximal TCR signaling. Besides the S345F and S520F mutations recently reported in cutaneous T-cell lymphoma, we identified an additional hotspot mutations (R48W, E1163K, and D1165H). The second most frequently mutated gene was PRKCB, encoding a member of the protein kinase C (PKC) family of proteins (PKCβ), a pivotal signaling molecule downstream of PLCγ. The frequent mutations of PKCβ were unexpected, because it is PKCθ that has been implicated in TCR signaling, whereas PKCβ has been more focused in the context of B-cell receptor signaling. Approximately 93% of the PRKCB mutations were confined to the catalytic domain with a prominent hotspot at D427, suggesting gain-of-function nature of these mutations. Consistent with this, when transduced with the D427N PKCβ mutant, HEK293T and/or Jurkat cells showed increased membrane translocation after PMA/Ionomycin-stimulation, enhanced IKK phosphorylation and p65 nuclear translocation, and augmented NF-κB transcription, compared to wild-type PKCβ-transduced cells. Thus, these PRKCB mutations are the first activating mutations of this family identified in human cancers. Downstream to PKC lies CARD11, a scaffolding protein required for antigen receptor-induced NF-κB activation. Although previously reported in B-cell lymphomas, CARD11 mutations were more common in ATL (24%). In B-cell lymphomas, mutations are largely limited to the coiled-coil (CC) domain, whereas in ATL, they were clustered not only within the CC domain, but also within the PKC-responsive inhibitory domain, showing a prominent mutational hotspot at E626. The inhibitory domain has been implicated in autoinhibition, whose deletion leads to constitutive activation of CARD11. Intriguingly, WGS identified small intragenic deletions confined to this domain (exons 14-17) in 4 cases (8%) without canonical mutations, and RNA-seq confirmed the skipping of the corresponding exons in these cases. Remarkably, CARD11 mutation significantly co-occurred with PRKCBmutations, suggesting potential functional synergism between these lesions. Actually, overexpression of wild-type CARD11 induced NF-κB activation, which was further augmented by E626K mutation. Similarly, when both CARD11 (E626K) and PRKCB (D427N) mutants were co-expressed, more enhanced NF-κB activation was observed. RNA-seq and follow-up RT-PCR screening also identified novel gene fusions in TCR / NF-κB pathway: five CTLA4-CD28 and three ICOS-CD28 fusions were observed in seven (7%) of the 105 cases examined, of whom one patient carried both chimeric fusions. WGS revealed tandem duplications of 2q33.2 segments containing CD28, CTLA4, and ICOS, compatible with the corresponding fusion transcripts. B7/CD28 co-signaling molecules, including CD28, CTLA4, and ICOS co-receptors, play pivotal roles in positive and negative regulations of TCR signaling. All the predicted chimeric proteins had the cytoplasmic part of CD28, and are expected to be expressed under the control of the regulatory element of CTLA4 or ICOS, likely leading to prolonged expression of CD28 co-stimulator. Our findings suggest that deregulated TCR / NF-κB pathway caused by genetic alterations is a hallmark of ATL pathogenesis. The predominance of gain-of-function mutations in this pathway offers good opportunities for exploiting these mutations for the targets of novel drugs to better manage patients. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Chugai: Honoraria, Research Funding; Shin-bio: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.113.113
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 9
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    Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia/Lymphoma
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2643-2643
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2643-2643
    Abstract: Adult T-cell leukemia/lymphoma (ATL) is a distinct subtype of peripheral T-cell neoplasms associated with human T-cell leukemia virus type-1 retrovirus. ATL includes a heterogeneous group of patients in terms of pathological and clinical features as well as prognosis, suggesting the presence of underlying molecular pathogenesis that could explain such heterogeneity among patients. Recently, we performed an integrated molecular analysis of a large number of ATL cases and delineated a comprehensive registry of gene mutations and other genetic/epigenetic lesions in ATL. In this study, we investigated possible correlations between these genetic/epigenetic lesions and clinical/pathological phenotypes in a large set of ATL patients, with a special focus on the impact of mutations and copy number alterations (CNAs) on clinical outcome. We analyzed a total of 361 ATL samples, including acute (n = 192), lymphoma (n = 66), chronic (n = 89), and smoldering (n = 14) subtypes, for recurrent mutations and CNAs. Each subtype had characteristic genetic/epigenetic features, suggesting a distinct molecular pathogenesis therein. Aggressive (acute and lymphoma) subtypes were characterized by a higher number of mutations and CNAs including focal amplifications/deletions, hyperploid status, and CIMP phenotype, compared with indolent (chronic and smoldering) tumors. Two mutations (TP53 and IRF4) and eight focal deletions involving 1p13 (CD58), 6p21 (HLA-B), 9p21 (CDKN2A), 10p11 (CCDC7), 13q32 (GPR183), 16q23 (WWOX), 17p13 (TP53), and 19q13 (CEBPA), were more common in aggressive ATL than in indolent ATL. In contrast, showing a similar mutational distribution to those found in large granular lymphocytic leukemia, STAT3 mutations were characteristic of the indolent diseases. Gene set enrichment analysis of RNA-seq data showed a significant enrichment of MYC pathway and genes regulating cell cycle and DNA repair in upregulated genes in aggressive ATL. Next, we assessed the impact of mutations and CNVs on prognosis among 215 ATL cases, for which survival data were available. In the entire cohort, mutation in CCR4 and IRF4, focal amplification in 9p24 (CD274) and 14q32 (BCL11B), and focal deletion in 9p21 (CDKN2A) were found to be significant predictors of poor overall survival, after adjustment for disease subtype and age. Multivariate analysis revealed that disease subtype (aggressive vs. indolent) was the most significant predictor of clinical outcome in ATL. Subsequent multivariate analysis according to disease subtype showed that within the patients with aggressive ATL, older age (≥ 70 years), CCR4 mutations, and 9p24 amplification were independently associated with an adverse outcome. Based on the number of the risk factors they owned, patients with aggressive ATL were classified into three categories showing marked difference in 3-year overall survival (OS) (P 〈 0.001): those with no risk factors (OS, 32%), with one risk factor (18%), and with two or more (0%). Among the patients with indolent ATL, we found IRF4 and TP53 mutations, 9p24 amplification, and deletions in 9p21 and 10p11 were independently associated with reduced survival. Interestingly, these alterations, except for 9p24 amplification, were also identified as genes more frequent in aggressive ATL. More importantly, based on these risk factors, the patients with indolent ATL can be classified into two categories showing very different prognostic profiles: patients with no risk factors (OS, 89%) and those with one or more risk factors (21%) (P 〈 0.001, HR = 16.8, 95% CI:5.4-52.5), suggesting that patients with indolent ATL having a genetic feature of the aggressive subtypes might genetically and biologically represent a distinct subset, which should be better managed as having an aggressive disease. Among these poor prognostic factors, 9p24 amplification and CCR4 mutation are especially interesting, because these lesions might be plausible targets of available agents, including anti-PD1/PD-L1 and anti-CCR4 antibodies. In conclusion, based on the comprehensive genetic profiling, we demonstrated that the known subtypes of ATL can be further classified into genetically and biologically distinct subsets of tumors characterized by discrete sets of genetic lesions and substantially different prognosis. Our results suggest that molecular profiling can improve the prediction of prognosis in ATL patients and better guide therapy. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Shin-bio: Honoraria; Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2643.2643
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 10
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    Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma
    American Society of Hematology ; 2018
    In:  Blood Vol. 131, No. 2 ( 2018-01-11), p. 215-225
    Details
    In: Blood, American Society of Hematology, Vol. 131, No. 2 ( 2018-01-11), p. 215-225
    Abstract: ATL subtypes are further classified into molecularly distinct subsets with different prognosis by genetic profiling. PD-L1 amplifications are a strong genetic predictor for worse outcome in both aggressive and indolent ATL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2017-01-761874
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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