Kooperativer Bibliotheksverbund

In: Leukemia, Springer Science and Business Media LLC, Vol. 36, No. 1 ( 2022-01), p. 90-99

Abstract: In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3 -ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole ( n  = 251, 55%), JMD and TKD1 (JMD/TKD1; n  = 117, 26%), and TKD1sole ( n  = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole ( P  = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively ( P  = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3 -ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-021-01323-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2008023-2

In: Leukemia, Springer Science and Business Media LLC, Vol. 36, No. 9 ( 2022-09), p. 2218-2227

Abstract: The aim of this study was to characterize the mutational landscape of patients with FLT3 -mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3 -mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1 : NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1 :treatment (with midostaurin exerting a beneficial effect in WT1 -mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3 -mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-022-01650-w

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1534-1534

Abstract: Background: Recently, the oral multitargeted small molecule FLT3 inhibitor midostaurin (M) was approved for treatment of FLT3-mutated AML in combination with standard chemotherapy. In the international RATIFY (NCT00651261) trial, addition of M led to superior overall and event-free survival compared to placebo, thus defining a new standard of care in this AML subset (Stone RM et al. NEJM 2017). Although not powered for subgroup analyses, M showed consistent effects across all FLT3 mutation strata [tyrosine kinase domain (TKD); internal tandem duplication (ITD) with low (0.05-0.7; ITDlow) or high ( 〉 0.7; ITDhigh) allelic ratio] suggesting significant off-target activity beyond FLT3 inhibition. Aim: We aimed to comprehensively profile the mutational landscape of FLT3 mutated (FLT3mut) AML in a large, well characterized cohort of patients (pts) treated within the RATIFY trial using a high-throughput targeted sequencing (HTS) approach. Methods: HTS was performed on the entire coding region of 262 genes involved in hematologic malignancies including 20 genes that encode kinases targeted by M (M kinome, MK). Pretreatment peripheral blood (PB; 14%) or bone marrow (BM; 86%) specimens were available from 475 (66%) of 717 FLT3mut AML RATIFY pts. Libraries were prepared using SureSelectXT custom solutions (Agilent). Paired-end sequencing was carried out on a HiSeq platform (Illumina). FLT3 mutation (mut) status was available for all pts [TKD: 24%; ITD: 76% (ITDlow: 45%; ITDhigh:31%)], and cytogenetic data for 454 pts (96%). Results: An average sequencing depth of 978x was obtained for all pts. In sum, 1815 mut (missense: 49%; indels: 40%; nonsense: 7%; other: 3%) were identified with a mean of 3.8 mut per pt (FLT3 strata; TKD: 4; ITDlow: 4; ITDhigh: 3.6).Overall, recurrent mut ( 〉 5% of all pts) were found in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), RUNX1 (11%), NRAS (11%), PTPN11 (9%), ASXL1 (8%), IDH1 (8%), IDH2 (7%; R140 only), and SMC1A (6%). In contrast, TP53 (1%) and biallelic CEPBA (1%) mut were rare events. This was also true for aberrations of the MK (7% in total) with KIT (2%), MAP3K11 (1%), and NTRK3 (1%) being most frequently mutated. When stratified according to FLT3mut type, mut in NRAS (24% vs 7%, p 〈 .0001), SMC1A (10% vs 4%, p=.02), and KIT (4% vs 1%, p=.02) occurred significantly more often in TKD than ITD groups, respectively, whereas WT1 (13% vs 24%, p=.018) was more frequently co-mutated in the ITD group. In general, pts in the TKD group had significantly more mut in genes encoding for cohesin (TKD: 29% vs ITD: 16%, p=.004) and signaling (TKD: 40% vs ITD: 24%, p=.001) proteins compared to ITD pts, who had significantly more mut in transcription genes (TKD: 37% vs ITD: 48%, p=.03). Based on the mut and cytogenetic data, we next sought to assign all FLT3mut pts to the 11 recently defined molecular AML classes (Papaemmanuil E et al. NEJM 2016). The majority fell into two classes, namely the NPM1 (N; 62%) and the chromatin-spliceosome (CS; 15%) classes, underscoring the significance of FLT3mut as the driver in these particular genomic classes. Other class-defining lesions were rare or absent in this cohort [inv(16): 2%; t(8;21): 2%; t(11q23;x): 2%; t(6;9): 1%, TP53-aneuploidy: 1%; CEBPAbiallelic: 1%; IDH2R172: 0%]. In 14% of all pts categorization was not possible (no or 〉 1 class-defining lesion), emphasizing the need for further refinement of this classification. When focusing on these two groups, N and CS had comparable FLT3mut patterns (TKD: 24% vs 21%; ITDlow: 44% vs 45%; ITDhigh: 32% vs 33%), whereas N more frequently correlated with a normal karyotype (N: 91% vs CS: 63%). With respect to clinical characteristics, no differences between N and CS in terms of age, white blood cells, platelets, PB and BM blasts, as well as history of MDS were observed. Conclusion: In this comprehensive sequencing approach, we could further delineate the molecular pattern of FLT3mut AML. Here, FLT3-ITD and -TKD groups exhibited remarkable differences in cooperating pathways, highlighting distinct biologic features in the leukemogenesis of FLT3mut AML. Overall, mut of MK genes were rare events, not fully explaining the complexity of M off-target effects. Understanding the underlying disease mechanism will potentially provide useful information on prognosis and prediction of response to M. Further analyses including correlation with clinical outcome are ongoing. Support: U10CA180821, U10CA180861, U10CA180882, U24CA196171 Disclosures Bullinger: Janssen: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Bayer Oncology: Research Funding. Gathmann:Novartis: Employment. Larson:Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Medeiros:Genentech: Employment; Celgene: Consultancy, Research Funding. Tallman:ADC Therapeutics: Research Funding; AROG: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding. Tiecke:Novartis: Employment. Pallaud:Novartis: Employment. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Stone:Otsuka: Consultancy; Jazz: Consultancy; Cornerstone: Consultancy; Fujifilm: Consultancy; Arog: Consultancy, Research Funding; Pfizer: Consultancy; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Ono: Consultancy; Orsenix: Consultancy; Merck: Consultancy; Argenx: Other: Data and Safety Monitoring Board; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Döhner:AROG Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-115842

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 435-435

Abstract: Introduction: Internal tandem duplication of the FLT3 gene (FLT3-ITD), resulting in duplication of 3 to more than hundreds of nucleotides, are present in approximately 25% of adults with newly diagnosed AML. Several studies have shown that ITD mutations are associated with poor prognosis due to a high relapse rate, in particular in case of a high mutant to wild-type allele ratio and/or insertion site in the beta1-sheet of the tyrosine kinase domain-1 (beta1-sheet). Aims: To investigate the relationship between ITD insertion site and patient outcome, Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive patients (pts) enrolled into the RATIFY trial (NCT00651261). Results: NGS identified 908 ITDs with up to 9 ITDs per case (1 ITD: n=210, 46.5%; 2 ITDs: n=131, 29.0%; 3 ITDs: n=58, 12.8%; 4 ITDs: n=24, 5.3%; 5 ITDs: n=18, 4.0%; 6 ITDs: n=3, 0.7%; 7 ITDs: n=7, 1.5%; 9 ITDs: n=1, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. According to the 4 functional groups, 488 ITDs (53.7%) were located within the juxtamembrane domain (JMD), 155 ITDs (17.1%) within the hinge region, 211 ITDs (23.2%) within the beta1-sheet, and 54 ITDs (5.9%) 3´of beta1-sheet. ITD size strongly correlated with insertion site, in that the more C-terminal the insertion site, the longer the size of the inserted fragment (P 〈 .001). In 242 pts (53.5%) featuring multiple ITD clones, 698 concurrent integration sites were delineated, with coexistent integration sites within JMD being the most frequent interaction (37%) followed by JMD and beta1-sheet (13.5%), and within beta1-sheet (7.8%). NPM1 mutations (NPM1mut) were present in 203/358 pts (56.7%). Correlation of ITD insertion site with NPM1mut revealed a significantly lower incidence of NPM1mut in pts with insertion located within the hinge region (50/106, 47.2% vs 153/252, 60.7%; P=.02) and 3´of beta1-sheet (14/41, 34.1% vs 189/317, 59.6%; P=.002), whereas NPM1mut were significantly more frequent in pts with insertions affecting JMD (143/235, 60.9% vs 60/123, 48.8%; P=.03). Clinical characteristics differing among the 4 functional ITD groups were gender and WBC. Pts with insertions 3´of beta1-sheet were predominantly male (28/46, 60.9% vs 178/406, 43.8%; P=.03); pts with JMD insertions exhibited lower WBC (median 36.5 vs 52.7 x109/L; P=.03). Complete remission (CR) was achieved within 60 days in 248/452 pts (54.9%). To evaluate the impact of ITD insertion site on response to induction, a logistic regression model was used. ITD insertion sites were categorized in (i) only in beta1-sheet, (ii) in beta1-sheet and other sites, and (iii) outside the beta1-sheet. Other variables were ITD mutant to wild-type allelic ratio (fragment analysis, cutoff at 0.5), number of ITDs per patient, log2 of WBC counts, age, NPM1mut, and midostaurin treatment. In this model, only number of ITDs predicted lower CR rate (OR, 0.72; 95% CI, 0.57-0.90), while NPM1mut was a favorable marker for CR (OR, 2.69; 95% CI, 1.70-4.28). Median follow-up for survival was 60.6 months (mo); median event free survival (EFS) and overall survival (OS) were 3.9 mo and 24.4 mo, respectively. The 4-year EFS and OS rates were 21.0% (95% CI, 17.2%-24.8%) and 42.6% (95% CI, 37.9%-47.4%), respectively. Survival analysis according to categorized insertion site groups showed that pts exhibiting insertion exclusively in the beta1-sheet had significantly inferior OS (P=.014) compared to the other two groups. Multivariate models for OS and EFS including hematopoietic stem-cell transplantation (HSCT) as a time-dependent covariate revealed WBC counts as unfavorable and NPM1mut as favorable for both endpoints; further unfavorable factors were older age and exclusive insertion in the beta1-sheet (HR, 1.49; 95% CI, 1.01-2.20) for OS and number of ITDs (HR, 1.15; 95% CI, 1.04-1.28) for EFS; HSCT was a favorable factor only for EFS (HR, 0.66; 95% CI, 0.44-0.99). Midostaurin treatment was associated with in trend improved EFS (HR, 0.81; 95% CI, 0.63-1.03) and OS (HR, 0.77; 95% CI, 0.57-1.02). Conclusions: In this large cohort of 452 FLT3-ITD mutated AML treated within the RATIFY trial the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed. Further analyses to investigate potential predictive effects of midostaurin treatment are ongoing. Support: U10CA180821, U10CA180882, U24CA196171, (CCSRI) #704970. Disclosures Du: Novartis: Employment. Gathmann:Novartis: Employment. Larson:Ariad/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Medeiros:Celgene: Consultancy, Research Funding; Genentech: Employment. Tallman:Orsenix: Other: Advisory board; Cellerant: Research Funding; AROG: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Tiecke:Novartis: Employment. Pallaud:Novartis: Employment. de Witte:Amgen: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Ehninger:Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Bullinger:Bristol-Myers Squibb: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Bayer Oncology: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Döhner:Pfizer: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Research Funding. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116149

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 135, No. 5 ( 2020-01-30), p. 371-380

Abstract: Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P & lt; .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019002697

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Nature, Springer Science and Business Media LLC, Vol. 555, No. 7697 ( 2018-03-22), p. 469-474

Type of Medium: Online Resource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/nature26000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 120714-3

detail.hit.zdb_id: 1413423-8

SSG: 11

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3445-3445

Abstract: Ionizing radiation is a common treatment option for cancer but its use is limited by the unpredictable and highly heterogeneous onset of late side effects, especially radiation-induced fibrosis. Clinically applicable biomarkers and effective treatments for radiation fibrosis are currently unavailable. In order to identify novel markers we ran a genome-wide DNA methylation screen in primary dermal fibroblasts obtained from breast cancer patients before intraoperative radiotherapy. Cells from patients developing fibrosis within a three-year follow up were compared to those without fibrosis (12 individuals per group). Illumina Infinium HumanMethylation450 BeadChip analysis revealed differentially methylated sites which are associated with fibrosis. Notably, we identified a differentially methylated region (DMR) at the diacylglycerol kinase alpha (DGKA) locus as a potential fibrosis marker. This DGKA DMR was confirmed using quantitative MassARRAY technology in 75 patient fibroblast samples. We first investigated whether high or low DNA methylation at this DGKA DMR affects cellular radiation response. Functional in vitro analysis showed that the methylation status of the DGKA DMR inversely correlated with its radiation-induced mRNA and protein expression as well as with its enzymatic activity. We next examined the DMR for its role as a regulatory site. The intragenically located DMR was identified as a potential enhancer sequence using chromatin immunoprecipitation (ChIP) for H3K4me1 and H3K27ac as well as luciferase reporter assays. Chromatin conformation capture (3C) analysis revealed interaction of this enhancer with the DGKA promoter in fibroblasts with low DNA methylation, and further ChIP experiments showed a DNA methylation-dependent recruitment of the profibrotic transcription factor Early Growth Response 1 (EGR1) to this site. We finally asked how epigenetically altered DGKA expression could impact on cellular processes relevant to fibrosis such as fibroblast transactivation or stress response. Results in primary fibroblasts showed that, in response to ionizing radiation and other stress factors, DGKA affects global levels of its substrate diacylglycerol, as well as expression of the fibroblast activation markers Alpha Smooth Muscle Actin (ACTA2) and collagen 1 (COL1A1). Upon overexpression of DGKA in HEK293T cells, a luciferase-based screening of 15 stress-responsive signaling reporters revealed functional consequences on several response pathways. In summary, DGKA has emerged as a novel, epigenetically regulated signaling protein that has a role in radiation fibrosis and may serve as a new biomarker and therapeutic target. Citation Format: Christoph Weigel, Marlon R. Veldwijk, Christopher C. Oakes, Petra Seibold, Alla Slynko, David B. Liesenfeld, Carsten Herskind, Elena Sperk, Axel Benner, Christoph Plass, Frederik Wenz, Jenny Chang-Claude, Peter Schmezer, Odilia Popanda. Diacylglycerol kinase alpha as a novel epigenetically regulated risk marker for radiotherapy-induced fibrosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3445. doi:10.1158/1538-7445.AM2015-3445

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2015-3445

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2015

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: The Lancet Oncology, Elsevier BV, Vol. 20, No. 11 ( 2019-11), p. 1576-1586

Type of Medium: Online Resource

ISSN: 1470-2045

URL: Article

DOI: 10.1016/S1470-2045(19)30503-0

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2049730-1

In: Nature Communications, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2016-03-11)

Abstract: Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha ( DGKA ). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/ncomms10893

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2016

detail.hit.zdb_id: 2553671-0