iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

Dannenmann, Benjamin and Klimiankou, Maksim and Oswald, Benedikt and Solovyeva, Anna and Mardan, Jehan and Nasri, Masoud and Ritter, Malte and Zahabi, Azadeh and Arreba-Tutusaus, Patricia and Mir, Perihan and Stein, Frederic and Kandabarau, Siarhei and Lachmann, Nico and Moritz, Thomas and Morishima, Tatsuya and Konantz, Martina and Lengerke, Claudia and Ripperger, Tim and Steinemann, Doris and Erlacher, Miriam and Niemeyer, Charlotte M. and Zeidler, Cornelia and Welte, Karl and Skokowa, Julia. (2021) iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia. Cell Stem Cell, 28 (5). pp. 906-922.e6.

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Official URL: https://edoc.unibas.ch/83866/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Stem Cells and Hematopoiesis (Lengerke)
UniBasel Contributors:Konantz, Martina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 Aug 2021 09:22
Deposited On:31 Aug 2021 09:22

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