zebrafish; EVI1; hematopoietic stem cells; hematopoiesis; xenotransplantation; developmental hematopoiesis; acute lymphoblastic leukemia
Konantz Martina, Müller Joëlle S., Lengerke Claudia (2019),
Stem Cell Mobilization Methods and Protocols, Springer New York, New York, NY.
Carapito Raphael, Konantz Martina, Paillard Catherine, Miao Zhichao, Pichot Angélique, Leduc Magalie S., Yang Yaping, Bergstrom Katie L., Mahoney Donald H., Shardy Deborah L., Alsaleh Ghada, Naegely Lydie, Kolmer Aline, Paul Nicodème, Hanauer Antoine, Rolli Véronique, Müller Joëlle S., Alghisi Elisa, Sauteur Loïc, Macquin Cécile, Morlon Aurore, Sancho Consuelo Sebastia, Amati-Bonneau Patrizia, Procaccio Vincent, et al. (2017), Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features, in
Journal of Clinical Investigation, 127(11), 4090-4103.
Paczulla Anna M., Dirnhofer Stephan, Konantz Martina, Medinger Michael, Salih Helmut R., Rothfelder Kathrin, Tsakiris Dimitrios A., Passweg Jakob R., Lundberg Pontus, Lengerke Claudia (2017), Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice, in
Haematologica, 102(5), 854-864.
Wang Hui, Schaefer Thorsten, Konantz Martina, Braun Martin, Varga Zsuzsanna, Paczulla Anna M., Reich Selina, Jacob Francis, Perner Sven, Moch Holger, Fehm Tanja N., Kanz Lothar, Schulze-Osthoff Klaus, Lengerke Claudia (2017), Prominent Oncogenic Roles of EVI1 in Breast Carcinoma, in
Cancer Research, 77(8), 2148-2160.
Paczulla Anna M, Dirnhofer Stephan, Konantz Martina, Medinger Michael, Salih Helmut R, Rothfelder Kathrin, Tsakiris Dimitrios A, Passweg Jakob R, Lundberg Pontus, Lengerke Claudia (2017), Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice., in
Haematologica, 102(5), 854-864.
Wang Hui, Schaefer Thorsten, Konantz Martina, Braun Martin, Varga Zsuzsanna, Paczulla Anna M, Reich Selina, Jacob Francis, Perner Sven, Moch Holger, Fehm Tanja N, Kanz Lothar, Schulze-Osthoff Klaus, Lengerke Claudia (2017), Prominent Oncogenic Roles of EVI1 in Breast Carcinoma., in
Cancer research, 77(8), 2148-2160.
Konantz Martina, Alghisi Elisa, Müller Joëlle S, Lenard Anna, Esain Virginie, Carroll Kelli J, Kanz Lothar, North Trista E, Lengerke Claudia (2016), Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence, in
The EMBO Journal, 35(21), 2315-2331.
Kanz Dirk, Konantz Martina, Alghisi Elisa, North Trista E., Lengerke Claudia (2016), Endothelial-to-hematopoietic transition: Notch-ing vessels into bloodEndothelial-to-hematopoietic transition, in
Annals of the New York Academy of Sciences, 1370(1), 97-108.
Kanz Dirk, Konantz Martina, Alghisi Elisa, North Trista E, Lengerke Claudia (2016), Endothelial-to-hematopoietic transition: Notch-ing vessels into blood., in
Annals of the New York Academy of Sciences, 1370(1), 97-108.
Konantz Martina, Alghisi Elisa, Müller Joëlle S, Lenard Anna, Esain Virginie, Carroll Kelli J, Kanz Lothar, North Trista E, Lengerke Claudia (2016), Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence., in
The EMBO journal, 35(21), 2315-2331.
SUMMARY OF THE RESEARCH PLANTranscription factors which direct blood cell development during embryogenesis (e.g. SCL, MLL, AML1/RUNX1) can reactivate expression in adult hematopoietic cells and induce malignant transformation (e.g. leukemia). We have previously identified the BMP-Wnt-CDX-HOX signaling pathway as an essential regulator of developmental hematopoiesis and have demonstrated involvement of CDX genes in the pathogenesis of human myeloid and lymphoid leukemia. To investigate the molecular targets of CDX2, we performed gene expression arrays on acute lymphoblastic leukemia (ALL) cells after CDX2 inhibition and identified the transcription factor EVI1 as a potential downstream gene. Consistently, CDX-mutant zebrafish embryo displayed reduced expression of the zebrafish homologue evi1.Originally identified as a retroviral insertion site in myeloid neoplasia, EVI1 has been intensively studied in mye-loid leukemia. Recently, we showed that EVI1 is also expressed in cell lines and primary samples from patients with lymphatic malignancies. In a pilot cohort of 31 patients with pediatric ALL, high EVI1 transcripts were de-tectable in ca. 10% of patients and associated with adverse clinical outcome (p=0.02). Knockdown of EVI1 in human ALL cells enhanced apoptosis sensitivity, suppressed in vivo leukemogenesis and enhanced overall sur-vival of xenotransplanted NSG mice (p<0.003). EVI1 also critically regulates embryonic blood development influencing primitive myelopoiesis (but not erythropoiesis) as well as stem cell formation, but the underlying molecular mechanisms are poorly understood. The current research proposal aims to further characterize the roles of EVI1 and the underlying molecular mechanisms in ALL and blood stem cell development. Following aims shall be addressed:1.To analyze functional roles of EVI1 in ALL (e.g. homing and migration, in vivo modulation of response to TRAIL-agonists, regulation of leukemia stem cells, behavior in zebrafish xenografts) and blood stem cell development (specification versus proliferation/survival)2.To identify EVI1 molecular targets and upstream regulatory mechanisms 3.To further analyze the prognostic significance of EVI1 expression in ALLSignificance: Elucidation of EVI1 driven functions and molecular mechanisms may provide rationales for novel therapies and targets for specific intervention in ALL. The obtained results may apply to several other tumor entities where EVI1 is a well-recognized oncogene. Analysis of EVI1 expression may contribute to the identifica-tion of patients with high-risk ALL.