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Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia

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Item Type:Article
Title:Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia
Creators Name:Eifert, T. and Hsu, C.J. and Becker, A.L. and Graessle, S. and Horne, A. and Bemmann, F. and Zhang, Q. and Heuser, M. and Vasioukhin, V. and Scholl, S. and Hochhaus, A. and Siegerist, F. and Endlich, N. and Bullinger, L. and Lane, S.W. and Haas, S. and Schnoeder, T.M and Heidel, F.H.
Abstract:Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members are conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Inactivation of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.
Keywords:Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Acute Myeloid Leukemia, Mammals, Animals, Mice
Publisher:Nature Publishing Group
Page Range:2027-2035
Date:October 2023
Official Publication:https://doi.org/10.1038/s41375-023-02005-9
PubMed:View item in PubMed

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