Kooperativer Bibliotheksverbund

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 96, No. 8 ( 2017-8), p. 1361-1372

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-017-3027-5

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2017

detail.hit.zdb_id: 1458429-3

In: Proteins: Structure, Function, and Bioinformatics, Wiley, Vol. 71, No. 4 ( 2008-06), p. 1955-1969

Abstract: We present a computational procedure for modeling protein–protein association and predicting the structures of protein–protein complexes. The initial sampling stage is based on an efficient Brownian dynamics algorithm that mimics the physical process of diffusional association. Relevant biochemical data can be directly incorporated as distance constraints at this stage. The docked configurations are then grouped with a hierarchical clustering algorithm into ensembles that represent potential protein–protein encounter complexes. Flexible refinement of selected representative structures is done by molecular dynamics simulation. The protein–protein docking procedure was thoroughly tested on 10 structurally and functionally diverse protein–protein complexes. Starting from X‐ray crystal structures of the unbound proteins, in 9 out of 10 cases it yields structures of protein–protein complexes close to those determined experimentally with the percentage of correct contacts 〉 30% and interface backbone RMSD 〈 4 Å. Detailed examination of all the docking cases gives insights into important determinants of the performance of the computational approach in modeling protein–protein association and predicting of protein–protein complex structures. Proteins 2008. © 2008 Wiley‐Liss, Inc.

Type of Medium: Online Resource

ISSN: 0887-3585 , 1097-0134

URL: Issue

URL: Article

DOI: 10.1002/prot.v71:4

DOI: 10.1002/prot.21867

Language: English

Publisher: Wiley

Publication Date: 2008

detail.hit.zdb_id: 1475032-6

SSG: 12

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 11 ( 2020-11), p. 2951-2963

Abstract: To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS , confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0929-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 5 ( 2021-05), p. 1301-1316

Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2 ). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p  = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% ( p   〈  0.001) vs 58.5% to 55.4% ( p  = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation of IDH1/2 mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-01043-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 224-224

Abstract: Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the detection of mutations in genes like DNA methyltransferase 3A (DNMT3A) and has recently been described to occur in healthy people and to predispose them to myeloid malignancies. DNMT3A is frequently mutated in acute myeloid leukemia (AML) and mutations have been detected in CD3 positive T-cells of some AML patients. In these patients DNMT3A mutations are early events that are likely to arise from CHIP. It is unknown how a history (hx) of CHIP influences the characteristics of AML patients and their response to therapy. We studied this question on the basis of a large cohort of DNMT3A mutated AML patients. Patients and Methods: 171 DNMT3A mutated AML patients (aged 18-87 years) were included in our study. 127 patients were treated intensively in trials of the AMLSHG and AMLSG. 34 patients received non-intensive therapy and for 10 patients the therapy is unknown. 148 patients carried a mutation at arginine R882. At the time of diagnosis and relapse samples were further sequenced for 54 genes involved in leukemia with next generation sequencing (NGS) on the Illumina platform. Library preparation of diagnostic samples was performed with the TruSight Myeloid sequencing panel (Illumina). T-cells (CD3+ CD11b- CD14- CD33-) were purified by flow cytometry from AML samples at the time of diagnosis. DNMT3A mutational analysis of T-cell samples and of mononuclear cells during remission or at relapse was performed also with ultra-deep sequencing using customized DNMT3A NGS primers. Presence of a DNMT3A mutation in sorted T cell populations was used as an indicator of a hx of CHIP. Results: A total of 40 patients (23%) were found to have the DNMT3A mutation in mononuclear cells and T-cells (hx of CHIP), while 131 patients (77%) had a DNMT3A mutation in mononuclear cells, but not T-cells (control cohort). Comparing these two patient cohorts revealed that significantly more patients in the hx of CHIP cohort had secondary AML (p=0.009), were older (p=0.005) and less likely to receive intensive treatment (p=0.047) while other clinical parameters did not significantly differ. Analysing the mutational profile of 54 genes revealed that the number of mutations per patient between these 2 groups was similar (median 5 vs 4 mutations, p=0.39). Patients with a hx of CHIP were significantly more likely to harbour mutations in TET2 (p=0.006), RUNX1 (p=0.004), SF3B1 (p=0.049), U2AF1 (p=0.015) but less likely to be NPM1 mutated (p=0.005). There was no significant difference in the allelic burden of DNMT3A in the CHIP hx (mean 43.6) vs control group (mean 44.5). The mean variant allele frequencies of DNMT3A, RUNX1 and NPM1 were highest (44, 45 and 43 respectively) as compared to other mutated genes like IDH1, IDH2 and FLT3 (32, 37 and 34). In relapse samples (n=11), the identical DNMT3A mutation could always be identified. However, patients with a hx of CHIP (n=2) had comparable allelic frequencies compared to diagnosis of mutated DNMT3A ( 〈 10% difference), but not NPM1 ( 〉 10% difference), while 7 out of 9 patients in the control group had a change in the allelic frequency at the time of relapse (mostly reduction). In all remission samples DNMT3A mutations could be identified with ultra-deep NGS but with variable allelic frequencies (0.13-50.01% in the control group, 0.25-70.14% in the hx of CHIP group). In the cohort of patients with intensive therapy there was no difference in CR rates between hx of CHIP and control groups (82 vs 90%, p=0.31). Overall survival (OS) was not influenced by a hx of CHIP (whole cohort: HR 1.09; 95%CI 0.67-1.79; P=.73; intensively treated cohort: HR 0.72; 95%CI 0.34-1.51; P=.38). Relapse-free survival (RFS) was also not different in the hx of CHIP vs the control group (HR 1.06; 95%CI 0.58-1.93; P=.85; intensively treated cohort only HR 0.91; 95%CI 0.46-1.78; P=.78). However, when looking at the influence of allogeneic stem cell transplantations (HSCT) on outcome in intensively treated patients, patients with a hx of CHIP showed abenefit from HSCT (HR 0.082; 95%CI 0.009-0.75; P= 0.027 Figure 1A) as compared to the control group (HR 0.68; 95%CI 0.39-1.21; P= 0.19, Figure 1B). Conclusion: AML patients with a hx of CHIP, as defined by mutated DNMT3A in T-cells, show a distinct clinical and molecular profile and may benefit from HSCT. Figure 1A. Figure 1A. Figure 1B. Figure 1B. Disclosures Bug: TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding. Fiedler:Pfizer, Amgen, Kolltan: Research Funding; Teva, Amgen, Astellas: Other: Travel Grant; Karyopharm: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.224.224

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. 16 ( 2018-10-18), p. 1703-1713

Abstract: Molecular measurable residual disease (MRD) assessment is not established in approximately 60% of acute myeloid leukemia (AML) patients because of the lack of suitable markers for quantitative real-time polymerase chain reaction. To overcome this limitation, we established an error-corrected next-generation sequencing (NGS) MRD approach that can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR). Targeted resequencing at the time of diagnosis identified a suitable mutation in 93% of the patients, covering 24 different genes. MRD was measured in CR samples from peripheral blood or bone marrow before alloHCT and identified 12 patients with persistence of an ancestral clone (variant allele frequency [VAF] & gt;5%). The remaining 96 patients formed the final cohort of which 45% were MRD+ (median VAF, 0.33%; range, 0.016%-4.91%). In competing risk analysis, cumulative incidence of relapse (CIR) was higher in MRD+ than in MRD− patients (hazard ratio [HR], 5.58; P & lt; .001; 5-year CIR, 66% vs 17%), whereas nonrelapse mortality was not significantly different (HR, 0.60; P = .47). In multivariate analysis, MRD positivity was an independent negative predictor of CIR (HR, 5.68; P & lt; .001), in addition to FLT3-ITD and NPM1 mutation status at the time of diagnosis, and of overall survival (HR, 3.0; P = .004), in addition to conditioning regimen and TP53 and KRAS mutation status. In conclusion, NGS-based MRD is widely applicable to AML patients, is highly predictive of relapse and survival, and may help refine transplantation and posttransplantation management in AML patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-02-829911

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. 138, No. Supplement 1 ( 2021-11-05), p. 2369-2369

Abstract: Introduction Selinexor is an exportin-1 (XPO1) inhibitor which forces the nuclear retention and functional activation of tumor suppressor proteins, inducing apoptosis in cancer cells. Overexpression of XPO-1 is common in many tumors, including acute myeloid leukemia (AML). A phase II study, "SAIL", of selinexor with cytarabine and idarubicin in patients with relapsed/refractory AML was conducted by Fiedler et al. showing a high remission rate. To identify molecular predictors of response and survival we evaluated the molecular mutations and their course in selinexor treated patients. Methods All 42 patients treated in the SAIL trial were eligible to participate in this translational study. The main criterion for inclusion in the present study was availability of DNA from bone marrow or peripheral blood at 3 time points: initial AML diagnosis, screening for the SAIL trial and first response assessment on day 28 of cycle 1. A custom TruSight myeloid sequencing panel was used to identify molecular mutations at diagnosis. Molecular response was defined as variant-allele frequency (VAF) & lt;1% in the follow-up sample after SAIL treatment independent of morphologic remission. Minimal residual disease (MRD) under selinexor maintenance treatment was quantified by error-corrected NGS with a limit of detection of 0.02%. Results Eighteen patients were included for whom DNA was available for all three time points. The median age was 47.5 years (29-72), median prior therapies was 3 (1-9). 13 patients had de novo and 5 secondary/therapy-related AML. ELN risk at first diagnosis was favorable in eight, intermediate in five and adverse in three patients. Only one course of SAIL treatment was administered to all patients. 8 patients achieved morphologic complete remission (CR) or CR with incomplete hematologic recovery (CRi). 13 patients proceeded to allogeneic hematopoietic cell transplantation (alloHCT) or donor lymphocyte infusion. The median overall survival was 0.69 years. The molecular profile showed a predominance of secondary AML-type mutations. No clear pattern was found between mutation status and morphologic CR or CRi (Figure 1). Molecular response to the SAIL induction treatment was found in 6 of 14 patients who had a molecular marker. Mutations in FLT3 (FLT3-TKD=1, FLT3-ITD=2), SF3B1 and TP53 were associated with molecular response, whereas mutations in GATA2, CUX1, TET2, BCOR, DNMT3A, RAD21, ASXL1, SRSF2, and WT1 were associated with resistance. When comparing the molecular characteristics of patients achieving CR/CRi (n=8) and all other patients (n=10), a trend to achieve CR was observed among patients with NPM1 mutations (P=0.094), whereas mutations in ASXL1 (P=0.09) and SRSF2 (P=0.09) were associated with refractoriness. One of the responding patients received selinexor as maintenance therapy for four years. The patient was diagnosed with de novo AML with normal cytogenetics, with SF3B1 and SRSF2 mutations. The patient received an HLA-identical transplant after myeloablative conditioning, but relapsed 6 years after alloHCT. One cycle of selinexor/chemotherapy was administered and the patient achieved CR. The patient continued selinexor maintenance treatment with 60 mg selinexor twice a week. SF3B1 and SRSF2 mutations were still present at the time of relapse and declined under SAIL treatment (Figure 2). The patient received one course of DLI (1x10 7CD3 +), which was tolerated well without signs of GvHD. MRD remained detectable 17 days after DLI. At 30 days after DLI treatment both MRD markers were negative. Under continued selinexor maintenance treatment MRD remained negative until last follow-up at 4.9 years after SAIL treatment. The patient tolerated selinexor well with short-term nausea and dysgeusia after selinexor intake. Selinexor maintenance treatment was stopped 4 years after SAIL treatment and the patient remains in CR 14 months after the end of maintenance. Conclusion In this small series, we found a correlation between FLT3, TP53 and SF3B1 mutation status and molecular response to selinexor/chemotherapy (SAIL). NPM1 mutations were associated with morphologic response to SAIL by trend. Finally, selinexor maintenance may have contributed to long-term disease control in a patient with relapsed AML, and long term therapy with selinexor is feasible. Figure 1 Figure 1. Disclosures Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Modemann: Servier: Honoraria, Other: Travel accomodation; Incyte: Other: Travel accomodation; Gilead: Other: Travel accomodation; Jazz Pharmaceuticals: Other: Travel accomodation; Novartis: Other: Travel accomodation; Teva: Other: Travel accomodation; Pfizer: Other: Travel accomodation; Amgen: Other: Travel accomodation; Daiichi Sankyo: Research Funding; Abbvie: Honoraria, Other: Travel accomodation. Bokemeyer: Merck KGaA: Honoraria; Sanofi: Consultancy, Honoraria, Other: Travel accomodation; Roche: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; BMS: Honoraria, Other: Travel accomodation, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Lilly/ImClone: Consultancy; Merck Serono: Consultancy, Other: Travel accomodation ; Bayer Schering Pharma: Consultancy; GSO: Consultancy; AOK Health insurance: Consultancy; Abbvie: Research Funding; ADC Therapeutics: Research Funding; Agile Therapeutics: Research Funding; Alexion Pharmaceuticals: Research Funding; Amgen: Research Funding; Apellis Pharmaceuticals: Research Funding; Astellas: Research Funding; BerGenBio: Research Funding; Blueprint Medicine: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Gilead Sciences: Research Funding; Gylcotope GmbH: Research Funding; GlaxoSmithKline: Research Funding; Inside: Research Funding; IO Biotech: Research Funding; Isofol Medical: Research Funding; Janssen-Cilag: Research Funding; Karyopharm Therapeutics: Research Funding; Lilly: Research Funding; Millenium: Research Funding; MSD: Research Funding; Nektar: Research Funding; Rafael Pharmaceuticals: Research Funding; Springworks Therapeutics: Research Funding; Taiho Pharmaceutical: Research Funding; Pfizer: Other. Ganser: Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thol: Astellas: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS/Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Heuser: Karyopharm: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Selinexor in patients with relapsed or refractory AML

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151091

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4938-4939

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-155836

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6070-6072

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-163035

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. S3 ( 2023-08), p. e51143d7-

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/01.HS9.0000972000.51143.d7

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2023

detail.hit.zdb_id: 2922183-3