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Only infant MLL rearranged leukemia is susceptible to an inhibition of PLK-1 by volasertib

ABSTRACT: MLL rearranged (MLLr) leukemia is in general characterized by a poor prognosis. Depending on the cell of origin, it can differ in the aggressiveness and the therapy response. For instance, in adults, volasertib blocking Polo-like-Kinase 1 (PLK-1), was well-tolerated, but only with limited success. On the other site, PLK-1 characterizes an infant MLLr signature indicating a potential specific sensitivity. By using our CRISPR/Cas9 MLLr model in hematopoietic stem and progenitor cells (HSPCs), derived from both human cord blood (huCB) and bone marrow (huBM), mimicking exactly the infant and adult patient diseases, we were able to shed light on this phenomenon. PLK-1 was significantly increased in our huCB compared to huBM model and healthy HPSCs, that was underpinned by analyzing infant and adult MLLr leukemia patients. Importantly, the expression height correlated with a functional response. Volasertib induced a significant dose-dependent decrease of proliferation and cell cycle arrest most pronounced in the infant model. Mechanistically, upon volasertib treatment, we uncovered a negative feedback only in the huBM model by compensatory upregulation of PLK-1. Our study emphasizes the importance of the cell of origin in leukemogenesis and provides the rationale to further evaluate volasertib as new therapeutic strategy in infant MLLr leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276639 | GEO | 2024/12/19

REPOSITORIES: GEO

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Only infant MLL rearranged leukemia is susceptible to an inhibition of PLK-1 by volasertib

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