Lens epithelium-derived growth factor/p75 (LEDGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1-rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia.

Center for Cancer Epigenetics The University of Texas MD Anderson Cancer Center Houston TX 77030

Center for Precision Environmental Health Baylor College of Medicine Houston TX 77030

Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston TX 77030

Department of Cell Biology Faculty of Science Charles University 116 36 Prague 1 Czech Republic

Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX 77030

Institute of Microbiology of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 166 10 Prague 6 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 166 10 Prague 6 Czech Republic;

Molecular Virology and Gene Therapy KU Leuven 3000 Leuven Belgium

Molecular Virology and Gene Therapy KU Leuven 3000 Leuven Belgium;

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The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function

Multivalency of nucleosome recognition by LEDGF

The TFIIS N-terminal domain (TND): a transcription assembly module at the interface of order and disorder

A ubiquitous disordered protein interaction module orchestrates transcription elongation

Unlike Its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival

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PDB
6EMO, 6EMR, 5YI9