Molekulare Pathogenese der chromosomalen Translokationen in akuten Leukämien

Abstract: In this work, several new and important findings have been presented about the molecular pathomechanisms of chromosomal translocations in acute leukemias.
Novel mouse models of ALL as E2A-PBX1 serve to identify new therapeutic targets as JAK/STAT and preBCR signaling pathway. Targeting preBCR-associated genes with small molecules in combination with the multiple tyrosine kinase inhibitor dasatinib seems to be a suitable strategy in the preBCR+ ALL subtype. Hence, we anticipated the predicted development of dasatinib resistance and identified novel genes and pathways involved in dasatinib sensitivity and resistance, which are susceptible of pharmacologic inhibition. Although dasatinib shows very promising activity in preBCR+ has not been yet established as standard therapy. Future research will be directed to elucidate mechanism of resistance of ALL to conventional chemotherapies using established approaches (functional unbiased shRNA screen, global transcriptomics, phospho-proteomics) in human and mouse leukemia models. These findings might be translated more rapidly into clinical care and might improve the treatment and prognosis of patients with acute leukemias. Additionally, further pathways were identified to confer resistance to dasatinib (as PI3K/AKT/MTOR signaling pathway) and will be validated and characterized to overcome resistance to targeted therapy and chemotherapy. Genome editing technology helped to establish novel models to study more accurately human MLL leukemias. Using different approaches, we identified and characterized signaling pathways and epigenetic regulators, on which AML1/ETO and MLL-rearranged leukemias were dependent. Future studies will address, how AML1/ETO modifies genome-wide the epigenetic landscape of leukemia cells and its impact on global transcriptome. Unbiased functional shRNA screen using libraries for epigenetic regulators will elucidate which factors are needed for AML1/ETO-mediated
leukemogenesis and which are susceptible of pharmacological intervention

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Edition: [Überarbeitete Version vom 10. März 2020]
• Language: Englisch
• Notes: Universität Freiburg, Habilitationsschrift, 2020

Classification and Topics

• Keyword: Translokation ; Leukämie ; Epigenetik

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2020
• Creator: Duque Afonso, Jesús
• Contributor: Duyster, Justus ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Further information

• DOI: 10.6094/UNIFR/166892
• URN: urn:nbn:de:bsz:25-freidok-1668923
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:56 PM CET