Search

Your search keyword '"Erlacher M"' showing total 193 results
Start Over Author "Erlacher M"
193 results on '"Erlacher M"'

1. Hämatologie

Author

Lauten, M., Erlacher, M., Knöfler, R., Speer, Christian P., editor, Gahr, Manfred, editor, and Dötsch, Jörg, editor

Published
2019
Full Text
View/download PDF

2. Topic: AS04-MDS Biology and Pathogenesis/AS04d-Somatic mutations: THE EVOLVING GENETIC LANDSCAPE OF PEDIATRIC MDS-EB

Author

Erlacher, M., primary, Yoshimi, A., additional, Stasik, S., additional, Ramamoorthy, S., additional, Lebrecht, D., additional, Noellke, P., additional, Goehring, G., additional, De Haas, V., additional, Starý, J., additional, Masetti, R., additional, Ussowicz, M., additional, Barzilai-Birenboim, S., additional, De Moerloose, B., additional, Kállay, K., additional, Buechner, J., additional, Dworzak, M., additional, Catala, A., additional, Hasle, H., additional, Schmugge, M., additional, Polychronopoulou, S., additional, Boďová, I., additional, Jahnukainen, K., additional, Smith, O., additional, Kavcic, M., additional, Turkiewicz, D., additional, Kjollerstrom, P., additional, Locatelli, F., additional, Wlodarski, M., additional, Thiede, C., additional, Strahm, B., additional, and Niemeyer, C., additional

Published
2023
Full Text
View/download PDF

3. Venetoclax-based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis

Author

Masetti, R., Baccelli, F., Leardini, D., Gottardi, F., Vendemini, F., Di Gangi, A., Becilli, M., Lodi, M., Tumino, M., Vinci, L., Erlacher, M., Strahm, B., Niemeyer, C. M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Masetti, R., Baccelli, F., Leardini, D., Gottardi, F., Vendemini, F., Di Gangi, A., Becilli, M., Lodi, M., Tumino, M., Vinci, L., Erlacher, M., Strahm, B., Niemeyer, C. M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

No abstract available

Published
2023

4. European standard clinical practice - Key issues for the medical care of individuals with familial leukemia

Author

Förster, A, Davenport, C, Duployez, N, Erlacher, M, Ferster, A, Fitzgibbon, J, Göhring, G, Hasle, H, Jongmans, M, Kolenova, A, Kronnie, G, Lammens, T, Mecucci, C, Mlynarski, W, Niemeyer, C, Sole, F, Szczepanski, T, Waanders, E, Biondi, A, Wlodarski, M, Schlegelberger, B, Ripperger, T, Förster, Alisa, Davenport, Claudia, Duployez, Nicolas, Erlacher, Miriam, Ferster, Alina, Fitzgibbon, Jude, Göhring, Gudrun, Hasle, Henrik, Jongmans, Marjolijn C, Kolenova, Alexandra, Kronnie, Geertruijte, Lammens, Tim, Mecucci, Cristina, Mlynarski, Wojciech, Niemeyer, Charlotte M, Sole, Francesc, Szczepanski, Tomasz, Waanders, Esmé, Biondi, Andrea, Wlodarski, Marcin, Schlegelberger, Brigitte, Ripperger, Tim, Förster, A, Davenport, C, Duployez, N, Erlacher, M, Ferster, A, Fitzgibbon, J, Göhring, G, Hasle, H, Jongmans, M, Kolenova, A, Kronnie, G, Lammens, T, Mecucci, C, Mlynarski, W, Niemeyer, C, Sole, F, Szczepanski, T, Waanders, E, Biondi, A, Wlodarski, M, Schlegelberger, B, Ripperger, T, Förster, Alisa, Davenport, Claudia, Duployez, Nicolas, Erlacher, Miriam, Ferster, Alina, Fitzgibbon, Jude, Göhring, Gudrun, Hasle, Henrik, Jongmans, Marjolijn C, Kolenova, Alexandra, Kronnie, Geertruijte, Lammens, Tim, Mecucci, Cristina, Mlynarski, Wojciech, Niemeyer, Charlotte M, Sole, Francesc, Szczepanski, Tomasz, Waanders, Esmé, Biondi, Andrea, Wlodarski, Marcin, Schlegelberger, Brigitte, and Ripperger, Tim

Abstract

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical

Published
2023

5. Second allogeneic stem cell transplantation can rescue a significant proportion of patients with JMML relapsing after first allograft

Author

Vinci, L., Flotho, C., Noellke, P., Lebrecht, D., Masetti, R., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Gungor, T., Stary, J., Turkiewicz, D., Ussowicz, M., de Heredia, C. D., Buechner, J., Jahnukainen, K., Kallay, K., Bodova, I., Smith, O. P., Zecca, M., Bresters, D., Lang, P., Masmas, T. N., Meisel, R., Pichler, H., Erlacher, M., Gohring, G., Locatelli, Franco, Strahm, B., Niemeyer, C. M., Yoshimi, A., Locatelli F. (ORCID:0000-0002-7976-3654), Vinci, L., Flotho, C., Noellke, P., Lebrecht, D., Masetti, R., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Gungor, T., Stary, J., Turkiewicz, D., Ussowicz, M., de Heredia, C. D., Buechner, J., Jahnukainen, K., Kallay, K., Bodova, I., Smith, O. P., Zecca, M., Bresters, D., Lang, P., Masmas, T. N., Meisel, R., Pichler, H., Erlacher, M., Gohring, G., Locatelli, Franco, Strahm, B., Niemeyer, C. M., Yoshimi, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2023

7. P051 - Topic: AS04-MDS Biology and Pathogenesis/AS04d-Somatic mutations: THE EVOLVING GENETIC LANDSCAPE OF PEDIATRIC MDS-EB

Author

Erlacher, M., Yoshimi, A., Stasik, S., Ramamoorthy, S., Lebrecht, D., Noellke, P., Goehring, G., De Haas, V., Starý, J., Masetti, R., Ussowicz, M., Barzilai-Birenboim, S., De Moerloose, B., Kállay, K., Buechner, J., Dworzak, M., Catala, A., Hasle, H., Schmugge, M., Polychronopoulou, S., Boďová, I., Jahnukainen, K., Smith, O., Kavcic, M., Turkiewicz, D., Kjollerstrom, P., Locatelli, F., Wlodarski, M., Thiede, C., Strahm, B., and Niemeyer, C.

Published
2023
Full Text
View/download PDF

8. P816: TRANSIENT MONOSOMY 7 IN SAMD9/9L SYNDROMES: IS IT SAFE TO WATCH AND WAIT?

Author

Erlacher, M., primary, Andresen, F., additional, Yoshimi, A., additional, Sukova, M., additional, Stary, J., additional, de Moerloose, B., additional, Dworzak, M., additional, Polychronopoulou, S., additional, Göhring, G., additional, Kratz, C., additional, van der Werff ten Bosch, J., additional, Seidel, M., additional, Strahm, B., additional, Wlodarski, M., additional, and Niemeyer, C., additional

Published
2022
Full Text
View/download PDF

9. S274: A NOVEL SUBTYPE OF ANEMIA CAUSED BY MUTATIONS IN TFRC GENE

Author

Colucci, S., primary, Venturi, V., additional, Nicole, F., additional, Jové Solavera, D., additional, Zimon, M., additional, Richter-Pechanska, P., additional, Hernandez, G., additional, Unal, S., additional, Gumruk, F., additional, Diaz-Conradi, A., additional, Romero-Cortadellas, L., additional, Ferrer-Cortès, X., additional, Olivella, M., additional, Erlacher, M., additional, Niemeyer, C., additional, Wiesel, T., additional, Pepperkok, R., additional, Fleming, M. D., additional, Kulozik, A. E., additional, Sanchez, M., additional, and Muckenthaler, M. U., additional

Published
2022
Full Text
View/download PDF

13. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Author

Sahoo S. S., Pastor V. B., Goodings C., Voss R. K., Kozyra E. J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O. P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B. D., Smith O., Haas V. D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P. D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R. D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L. M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M. L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M. R., Sauer M. G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M. H., Meisel R., Schulz A., Cario G., Panda P. K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C. M., Wlodarski M. W., Sahoo S.S., Pastor V.B., Goodings C., Voss R.K., Kozyra E.J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O.P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B.D., Smith O., Haas V.D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P.D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R.D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L.M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M.L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M.R., Sauer M.G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M.H., Meisel R., Schulz A., Cario G., Panda P.K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C.M., Wlodarski M.W., and Clinical Genetics

Subjects
Oncology, Male, medicine.medical_specialty, Monosomy, Adolescent, Somatic cell, Medizin, Bone Marrow Cells, Kaplan-Meier Estimate, General Biochemistry, Genetics and Molecular Biology, Germline, Article, Clonal Evolution, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Child, Germ-Line Mutation, Chromosome 7 (human), Cytopenia, clonal hemopoiesis, business.industry, Myelodysplastic syndromes, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, High-Throughput Nucleotide Sequencing, Infant, General Medicine, medicine.disease, GATA2 Transcription Factor, SAMD9 and SAMD9L mutations, Pediatric Myelodysplastic syndromes, medicine.anatomical_structure, HEK293 Cells, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Myelodysplastic Syndromes, Female, Bone marrow, Clonal Hematopoiesis, Single-Cell Analysis, business
Abstract

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.

Published
2021

14. P47 - Topic: AS07-Singular Entities/Subtypes/AS07c-Hereditary MDS including predisposition syndromes: HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN AND ADOLESCENTS WITH GATA2-RELATED MYELODYSPLASTIC SYNDROME

Author

Bortnick, R., Wlodarski, M., De Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Stary, J., Turkiewicz, D., Ussowicz, M., Kozyra, E., Albert, M., Bader, P., Bordon, V., Cario, G., Beier, R., Schulte, J., Bresters, D., Mueller, I., Pichler, H., Sedlacek, P., Sauer, M., Zecca, M., Göhring, G., Yoshimi, A., Noellke, P., Erlacher, M., Locatelli, F., Niemeyer, C., and Strahm, B.

Published
2021
Full Text
View/download PDF

15. O27 - Topic: AS06-Prognosis/AS06b-Predictive factors of response to treatment: OUTCOMES OF RELAPSED JUVENILE MYELOMONOCYTIC LEUKEMIA: THE ROLE OF SECOND HEMATOPOIETIC STEM CELL TRANSPLANTATION

Author

Yoshimi, A., Vinci, L., Flotho, C., Noellke, P., Erlacher, M., Lebrecht, D., Masetti, R., De Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Schmugge, M., Stary, J., Turkiewicz, D., Ussowicz, M., Catala, A., Buechner, J., Jahnukainen, K., Kállay, K., Fabri, O., Smith, O., Göhring, G., Locatelli, F., Strahm, B., and Niemeyer, C.

Published
2021
Full Text
View/download PDF

17. O05 - Topic: AS04-MDS Biology and Pathogenesis/AS04b-Clonal diversity & evolution: SOMATIC GENETIC RESCUE IN SAMD9/SAMD9L MDS PREDISPOSITION SYNDROMES

Author

Sahoo, S., Pastor, V., Goodings, C., Noellke, P., Dworzak, M., Stary, J., Locatelli, F., Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kállay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O., Fabri, O., Barzilai, S., De Haas, V., Baumann, I., Schwarz-Furlan, S., Göhring, G., Yoshimi, A., Flotho, C., Strahm, B., Erlacher, M., Niemeyer, C., and Wlodarski, M.

Published
2021
Full Text
View/download PDF

18. Topic: AS07-Singular Entities/Subtypes/AS07c-Hereditary MDS including predisposition syndromes

Author

Bortnick, R., primary, Wlodarski, M., additional, De Haas, V., additional, De Moerloose, B., additional, Dworzak, M., additional, Hasle, H., additional, Masetti, R., additional, Stary, J., additional, Turkiewicz, D., additional, Ussowicz, M., additional, Kozyra, E., additional, Albert, M., additional, Bader, P., additional, Bordon, V., additional, Cario, G., additional, Beier, R., additional, Schulte, J., additional, Bresters, D., additional, Mueller, I., additional, Pichler, H., additional, Sedlacek, P., additional, Sauer, M., additional, Zecca, M., additional, Göhring, G., additional, Yoshimi, A., additional, Noellke, P., additional, Erlacher, M., additional, Locatelli, F., additional, Niemeyer, C., additional, and Strahm, B., additional

Published
2021
Full Text
View/download PDF

19. Topic: AS06-Prognosis/AS06b-Predictive factors of response to treatment

Author

Yoshimi, A., primary, Vinci, L., additional, Flotho, C., additional, Noellke, P., additional, Erlacher, M., additional, Lebrecht, D., additional, Masetti, R., additional, De Haas, V., additional, De Moerloose, B., additional, Dworzak, M., additional, Hasle, H., additional, Schmugge, M., additional, Stary, J., additional, Turkiewicz, D., additional, Ussowicz, M., additional, Catala, A., additional, Buechner, J., additional, Jahnukainen, K., additional, Kállay, K., additional, Fabri, O., additional, Smith, O., additional, Göhring, G., additional, Locatelli, F., additional, Strahm, B., additional, and Niemeyer, C., additional

Published
2021
Full Text
View/download PDF

21. Topic: AS04-MDS Biology and Pathogenesis/AS04b-Clonal diversity & evolution

Author

Sahoo, S., primary, Pastor, V., additional, Goodings, C., additional, Noellke, P., additional, Dworzak, M., additional, Stary, J., additional, Locatelli, F., additional, Masetti, R., additional, Schmugge, M., additional, De Moerloose, B., additional, Catala, A., additional, Kállay, K., additional, Turkiewicz, D., additional, Hasle, H., additional, Buechner, J., additional, Jahnukainen, K., additional, Ussowicz, M., additional, Polychronopoulou, S., additional, Smith, O., additional, Fabri, O., additional, Barzilai, S., additional, De Haas, V., additional, Baumann, I., additional, Schwarz-Furlan, S., additional, Göhring, G., additional, Yoshimi, A., additional, Flotho, C., additional, Strahm, B., additional, Erlacher, M., additional, Niemeyer, C., additional, and Wlodarski, M., additional

Published
2021
Full Text
View/download PDF

23. Publisher Correction: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes (Nature Medicine, (2021), 27, 10, (1806-1817), 10.1038/s41591-021-01511-6)

Author

Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., and Wlodarski, M. W.

Subjects
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, SAMD9/SAMD9L syndromes
Published
2021

25. Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome

Author

Bortnick, R., Wlodarski, M., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Stary, J., Turkiewicz, D., Ussowicz, M., Kozyra, E., Albert, M., Bader, P., Bordon, V., Cario, G., Beier, R., Schulte, J., Bresters, D., Muller, I., Pichler, H., Sedlacek, P., Sauer, M. G., Zecca, M., Gohring, G., Yoshimi, A., Noellke, P., Erlacher, M., Locatelli, Franco, Niemeyer, C. M., Strahm, B., Locatelli F. (ORCID:0000-0002-7976-3654), Bortnick, R., Wlodarski, M., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Stary, J., Turkiewicz, D., Ussowicz, M., Kozyra, E., Albert, M., Bader, P., Bordon, V., Cario, G., Beier, R., Schulte, J., Bresters, D., Muller, I., Pichler, H., Sedlacek, P., Sauer, M. G., Zecca, M., Gohring, G., Yoshimi, A., Noellke, P., Erlacher, M., Locatelli, Franco, Niemeyer, C. M., Strahm, B., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (−7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and −7 (DFS 67%). Comparing outcome of GATA2mut with GATA2wt patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with −7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.

Published
2021

26. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Author

Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., Locatelli F. (ORCID:0000-0002-7976-3654), Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

Published
2021

27. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

Author

Kozyra, E., Pastor, V., Lefkopoulos, S., Sahoo, S., Busch, H., Voss, R., Erlacher, M., Lebrecht, D., Szvetnik, E., Hirabayashi, S., Pasaulienė, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kállay, K., Masetti, R., Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Starý, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Dereka, M., Göhring, G., Flotho, C., Strahm, B., Locatelli, F., Niemeyer, C., Trompouki, E., Wlodarski, M., and EWOG-MDS, W.

Abstract

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Published
2020

29. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

Author

Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., Erlacher, M., Lebrecht, D., Szvetnik, E. A., Hirabayashi, S., Pasauliene, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kallay, K., Masetti, R., De Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Stary, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Derecka, M., Gohring, G., Flotho, C., Strahm, B., Locatelli, Franco, Niemeyer, C. M., Trompouki, E., Wlodarski, M. W., Locatelli F. (ORCID:0000-0002-7976-3654), Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., Erlacher, M., Lebrecht, D., Szvetnik, E. A., Hirabayashi, S., Pasauliene, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kallay, K., Masetti, R., De Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Stary, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Derecka, M., Gohring, G., Flotho, C., Strahm, B., Locatelli, Franco, Niemeyer, C. M., Trompouki, E., Wlodarski, M. W., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Published
2020

31. Structure of the core Vaccinia Virus DNA-dependent RNA polymerase complex

Author

Grimm, C., primary, Hillen, H.S., additional, Bedenk, K., additional, Bartuli, J., additional, Neyer, S., additional, Zhang, Q., additional, Huettenhofer, A., additional, Erlacher, M., additional, Dienemann, C., additional, Schlosser, A., additional, Urlaub, H., additional, Boettcher, B., additional, Szalay, A., additional, Cramer, P., additional, and Fischer, U., additional

Published
2019
Full Text
View/download PDF

32. Structure of the complete Vaccinia DNA-dependent RNA polymerase complex

Author

Grimm, C., primary, Hillen, S.H., additional, Bedenk, K., additional, Bartuli, J., additional, Neyer, S., additional, Zhang, Q., additional, Huettenhofer, A., additional, Erlacher, M., additional, Dienemann, C., additional, Schlosser, A., additional, Urlaub, H., additional, Boettcher, B., additional, Szalay, A.A., additional, Cramer, P., additional, and Fischer, U., additional

Published
2019
Full Text
View/download PDF

34. Impaired human hematopoiesis due to a cryptic intronic splicing mutation

Author

Abdulhay, N.J., Fiorini, C., Verboon, J.M., Ludwig, L.S., Ulirsch, J.C., Zieger, B., Lareau, C.A., Mi, X., Roy, A., Obeng, E.A., Erlacher, M., Gupta, N., Gabriel, S.B., Ebert, B.L., Niemeyer, C.M., Khoriaty, R.N., Ancliff, P., Gazda, H.T., Wlodarski, M.W., and Sankaran, V.G.

Subjects
Cancer Research
Abstract

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.

Published
2019

37. PF677 DNA HYPERMETHYLATION EMERGES AS THE STRONGEST PREDICTOR FOR POOR OUTCOME AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML)

Author

Niemeyer, C.M., primary, Flotho, C., additional, Lipka, D.B., additional, Buechner, J., additional, Catala, A., additional, De Haas, V., additional, De Moerloose, B., additional, Dworzak, M., additional, Fabri, O., additional, Hasle, H., additional, Jahnukainen, K., additional, Kállay, K., additional, Masetti, R., additional, Schmugge, M., additional, Smith, O.P., additional, Stary, J., additional, Turkiewicz, D., additional, Ussowicz, M., additional, Schoenung, M., additional, Erlacher, M., additional, Yoshimi, A., additional, Bierings, M., additional, Bordon, V., additional, Diaz-de-Heredia, C., additional, Horakova, J., additional, Lankaster, A.C., additional, Masmas, T., additional, Meisel, R., additional, O’Marcaigh, A., additional, Roessig, C., additional, Peters, A., additional, Pichler, H., additional, Sauer, M., additional, Sedlacek, P., additional, Zecca, M., additional, Noellke, P., additional, Strahm, B., additional, and Locatelli, F., additional

Published
2019
Full Text
View/download PDF

38. S861 LOSS OF THE F-BOX PROTEIN NIPA CAUSES BONE MARROW FAILURE

Author

Kreutmair, S., primary, Erlacher, M., additional, Andrieux, G., additional, Istvanffy, R., additional, Kawaguchi, H., additional, Follo, M., additional, Wlodarski, M., additional, Baumann, I., additional, Pfeifer, D., additional, Dierks, C., additional, Zeiser, R., additional, Schindler, D., additional, Schmitt-Graeff, A., additional, Boerries, M., additional, Niemeyer, C., additional, Oostendorp, R., additional, Duyster, J., additional, and Illert, A.L., additional

Published
2019
Full Text
View/download PDF

39. PS1326 IMPLEMENTATION OF FUNCTIONAL ASSAYS TO CHARACTERIZE AND DETERMINE THE CLINICAL IMPACT OF RUNX1 VARIANTS OF UNCERTAIN SIGNIFICANCE IN SPORADIC DISEASES AS WELL AS IN THE CONTEXT OF FPDMM

Author

Decker, M., primary, Lammens, T., additional, Ferster, A., additional, Godley, L., additional, Erlacher, M., additional, Yoshimi, A., additional, Niemeyer, C.M., additional, Steinemann, D., additional, Schlegelberger, B., additional, Illig, T., additional, and Ripperger, T., additional

Published
2019
Full Text
View/download PDF

44. THU0040 Enhancement of early human b cell development by jak inhibition

Author

Thiel, J., primary, Venhoff, N., additional, Janowska, I., additional, Troilo, A., additional, Frede, N., additional, Erlacher, M., additional, Kunze, M., additional, Lorenzetti, R., additional, Staniek, J., additional, Bannert, B., additional, Kyburz, D., additional, Glaser, C., additional, Schleyer, M.-T., additional, Voll, R.E., additional, and Rizzi, M., additional

Published
2018
Full Text
View/download PDF

49. How cell death shapes cancer

Author

Labi, V. and Erlacher, M.

Subjects
Cancer Research
Abstract

Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results