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  • Functional and clinical characterization of the alternatively spliced isoform AML1-ETO9a in adult patients with translocation t(8;21)(q22; q22.1) acute myeloid leukemia (AML) LEUKEMIA Agrawal, M., Schwarz, P., Giaimo, B., Bedzhov, I., Corbacioglu, A., Weber, D., Gaidzik, V. I., Jahn, N., Ruecker, F. G., Schroeder, T., Kindler, T., Wattad, M., Goetze, K., Luebbert, M., Salwender, H., Ringhoffer, M., Lange, E., Koller, E., Thol, F., Heuser, M., Ganser, A., Bullinger, L., Paschka, P., Doehner, H., Geiger, H., Borggrefe, T., Doehner, K., Oswald, F. 2020; 34 (2): 630–34

    View details for DOI 10.1038/s41375-019-0551-4

    View details for Web of Science ID 000523481800028

    View details for PubMedID 31462736

    View details for PubMedCentralID PMC7214266

  • Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1) LEUKEMIA Meyer, T., Jahn, N., Lindner, S., Roehner, L., Dolnik, A., Weber, D., Scheffold, A., Koepff, S., Paschka, P., Gaidzik, V. I., Heckl, D., Wiese, S., Ebert, B. L., Doehner, H., Bullinger, L., Doehner, K., Kroenke, J. 2020; 34 (2): 404–15

    Abstract

    BRCA1/BRCA2-containing complex 3 (BRCC3) is a Lysine 63-specific deubiquitinating enzyme (DUB) involved in inflammasome activity, interferon signaling, and DNA damage repair. Recurrent mutations in BRCC3 have been reported in myelodysplastic syndromes (MDS) but not in de novo AML. In one of our recent studies, we found BRCC3 mutations selectively in 9/191 (4.7%) cases with t(8;21)(q22;q22.1) AML but not in 160 cases of inv(16)(p13.1q22) AML. Clinically, AML patients with BRCC3 mutations had an excellent outcome with an event-free survival of 100%. Inactivation of BRCC3 by CRISPR/Cas9 resulted in improved proliferation in t(8;21)(q22;q22.1) positive AML cell lines and together with expression of AML1-ETO induced unlimited self-renewal in mouse hematopoietic progenitor cells in vitro. Mutations in BRCC3 abrogated its deubiquitinating activity on IFNAR1 resulting in an impaired interferon response and led to diminished inflammasome activity. In addition, BRCC3 inactivation increased release of several cytokines including G-CSF which enhanced proliferation of AML cell lines with t(8;21)(q22;q22.1). Cell lines and primary mouse cells with inactivation of BRCC3 had a higher sensitivity to doxorubicin due to an impaired DNA damage response providing a possible explanation for the favorable outcome of BRCC3 mutated AML patients.

    View details for DOI 10.1038/s41375-019-0578-6

    View details for Web of Science ID 000523481800009

    View details for PubMedID 31576005

    View details for PubMedCentralID PMC7214237

  • Impact of gemtuzumab ozogamicin on MRD and relapse risk in NPM1 mutated AML patients: results from the AMLSG 09-09 Trial. Blood Kapp-Schwoerer, S., Weber, D., Corbacioglu, A., Gaidzik, V. I., Paschka, P., Krönke, J., Theis, F., Rücker, F. G., Teleanu, M. V., Panina, E., Jahn, N., Herzig, J. K., Kubanek, L., Schrade, A., Gohring, G., Fiedler, W., Kindler, T., Schroeder, T., Mayer, K., Lübbert, M., Wattad, M., Götze, K., Horst, H. A., Koller, E., Wulf, G. G., Schleicher, J., Bentz, M., Krauter, J., Bullinger, L., Krzykalla, J., Benner, A., Schlenk, R. F., Thol, F., Heuser, M., Ganser, A., Döhner, H., Döhner, K. 2020

    Abstract

    Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1 mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TL) by RQ-PCR and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TL and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase III AMLSG 09-09 trial. 3733 bone marrow (BM) and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after two treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity consistently revealed as poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TL were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly higher proportion of patients achieving MRD negativity at EOT (56% vs 41%; P=.01). The betterreduction of NPM1mut TL after two treatment cycles in MRD-positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR 29.3% vs 45.7%, P=.009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction of NPM1mut TL across all treatment cycles leading to a significantly lower relapse rate. The AMLSG 09-09 trial was registered at www.clinicaltrials.gov as #NCT00893399.

    View details for DOI 10.1182/blood.2020005998

    View details for PubMedID 32812041

  • Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication. Blood advances Jahn, N., Terzer, T., Sträng, E., Dolnik, A., Cocciardi, S., Panina, E., Corbacioglu, A., Herzig, J., Weber, D., Schrade, A., Götze, K., Schröder, T., Lübbert, M., Wellnitz, D., Koller, E., Schlenk, R. F., Gaidzik, V. I., Paschka, P., Rücker, F. G., Heuser, M., Thol, F., Ganser, A., Benner, A., Döhner, H., Bullinger, L., Döhner, K. 2020; 4 (24): 6342–52

    Abstract

    Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

    View details for DOI 10.1182/bloodadvances.2020002673

    View details for PubMedID 33351131

  • Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group BLOOD Ruecker, F. G., Agrawal, M., Corbacioglu, A., Weber, D., Kapp-Schwoerer, S., Gaidzik, V. I., Jahn, N., Schroeder, T., Wattad, M., Luebbert, M., Koller, E., Kindler, T., Goetze, K., Ringhoffer, M., Westermann, J., Fiedler, W., Horst, H. A., Greil, R., Schroers, R., Mayer, K., Heinicke, T., Krauter, J., Schlenk, R. F., Thol, F., Heuser, M., Ganser, A., Bullinger, L., Paschka, P., Doehner, H., Doehner, K., German Austrian Acute Myeloid Leuk 2019; 134 (19): 1608–18

    Abstract

    We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.

    View details for DOI 10.1182/blood.2019001425

    View details for Web of Science ID 000495894200009

    View details for PubMedID 31554635

  • Impact of NPM1/FLT3-ITD genotypes defined by the2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood Döhner, K., Thiede, C., Jahn, N., Panina, E., Gambietz, A., Larson, R. A., Prior, T. W., Marcucci, G., Jones, D., Krauter, J., Heuser, M., Voso, M. T., Ottone, T., Nomdedeu, J. F., Mandrekar, S. J., Klisovic, R., Wei, A. H., Sierra, J., Sanz, M. A., Brandwein, J., de Witte, T. M., Jansen, J. H., Niederwieser, D., Appelbaum, F., Medeiros, B. C., Tallman, M. S., Schlenk, R. F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Gathmann, I., Benner, A., Pallaud, C., Stone, R. M., Döhner, H., Bloomfield, C. D. 2019

    Abstract

    Patients with AML harboring FLT3 internal tandem duplications (ITD) have poor outcomes, in particular AML with a high ({greater than or equal to}0.5) mutant-to-wildtype allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined four 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 evaluating the addition of midostaurin to standard chemotherapy. The four NPM1/FLT3-ITD genotypes significantly differed 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 one or two induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly between 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<0.001). 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.

    View details for DOI 10.1182/blood.2019002697

    View details for PubMedID 31826241

  • Incidence and prognostic impact of ASXL2 mutations in adult acute myeloid leukemia patients with t(8;21)(q22;q22): a study of the German-Austrian AML Study Group LEUKEMIA Jahn, N., Agrawal, M., Bullinger, L., Weber, D., Corbacioglu, A., Gaidzik, V. I., Schmalbrock, L., Thol, F., Heuser, M., Krauter, J., Goehring, G., Kuendgen, A., Fiedler, W., Wattad, M., Held, G., Koehne, C., Horst, H., Luebbert, M., Ganser, A., Schlenk, R. F., Doehner, H., Doehner, K., Paschka, P. 2017; 31 (4): 1012–15

    View details for DOI 10.1038/leu.2017.18

    View details for Web of Science ID 000398261800033

    View details for PubMedID 28090090

  • Intermediate Monocytes but Not TIE2-Expressing Monocytes Are a Sensitive Diagnostic Indicator for Colorectal Cancer PLOS ONE Schauer, D., Starlinger, P., Reiter, C., Jahn, N., Zajc, P., Buchberger, E., Bachleitner-Hofmann, T., Bergmann, M., Stift, A., Gruenberger, T., Brostjan, C. 2012; 7 (9): e44450

    Abstract

    We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing monocytes (TEMs) in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N = 32) and in colorectal carcinoma patients with localized (N = 24) or metastatic (N = 37) disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes) the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer.

    View details for DOI 10.1371/journal.pone.0044450

    View details for Web of Science ID 000308577600056

    View details for PubMedID 22973451

    View details for PubMedCentralID PMC3433422