iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia
| Autor: | Charlotte M. Niemeyer, Perihan Mir, Azadeh Zahabi, Cornelia Zeidler, Malte U Ritter, Tim Ripperger, Masoud Nasri, Siarhei Kandabarau, Anna Solovyeva, Benjamin Dannenmann, Benedikt Oswald, Maksim Klimiankou, Doris Steinemann, Patricia Arreba-Tutusaus, Jehan Mardan, Nico Lachmann, Julia Skokowa, Miriam Erlacher, Karl Welte, Thomas Moritz, Martina Konantz, Frederic Stein, Tatsuya Morishima, Claudia Lengerke |
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| Rok vydání: | 2021 |
| Předmět: |
Neutropenia
Induced Pluripotent Stem Cells Biology Leukemogenic 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine hemic and lymphatic diseases Genetics medicine Congenital Bone Marrow Failure Syndromes Humans Progenitor cell Congenital Neutropenia neoplasms BAALC 030304 developmental biology 0303 health sciences Bone marrow failure Myeloid leukemia Oncogenes Cell Biology medicine.disease Neoplasm Proteins Leukemia Myeloid Acute Haematopoiesis RUNX1 chemistry Mutation Cancer research Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell. 28:906-922.e6 |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2021.03.023 |
| Popis: | Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome that can evolve to acute myeloid leukemia (AML). Mutations in CSF3R and RUNX1 are frequently observed in CN patients, although how they drive the transition from CN to AML (CN/AML) is unclear. Here we establish a model of stepwise leukemogenesis in CN/AML using CRISPR-Cas9 gene editing of CN patient-derived iPSCs. We identified BAALC upregulation and resultant phosphorylation of MK2a as a key leukemogenic event. BAALC deletion or treatment with CMPD1, a selective inhibitor of MK2a phosphorylation, blocked proliferation and induced differentiation of primary CN/AML blasts and CN/AML iPSC-derived hematopoietic stem and progenitor cells (HSPCs) without affecting healthy donor or CN iPSC-derived HSPCs. Beyond detailing a useful method for future investigation of stepwise leukemogenesis, this study suggests that targeting BAALC and/or MK2a phosphorylation may prevent leukemogenic transformation or eliminate AML blasts in CN/AML and RUNX1 mutant BAALC(hi) de novo AML. |
| Databáze: | OpenAIRE |
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