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

Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members appear to be 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. Loss of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in leukemic cells. Finally, 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. Overall design: Comparative gene expression profiling analysis of RNA-seq data for FLT3-ITD/ITD Llgl1-WT/WT Mx-Cre+ LSK (Lineage-, Sca-1-high, cKit-high) cells, FLT3-ITD/ITD Llgl1-WT/WT Mx-Cre- LSK cells and FLT3-ITD/ITD Llgl1-/- Mx-Cre+ LSK cells.