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LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis

Sara El Ashkar, Juerg Schwaller, Tim Pieters, Steven Goossens, Jonas Demeulemeester, Frauke Christ, Siska Van Belle, Sabine Juge, Nancy Boeckx, Alan Engelman, Pieter Van Vlierberghe, Zeger Debyser and Jan De Rijck

Key points

  • LEDGF/p75, an important cofactor required for MLL-rearranged leukemia, is not essential for steady-state hematopoiesis.

  • Loss of LEDGF/p75 blocks the development of MLL-rearranged leukemia supporting the MLL-LEDGF/p75 interaction as a new therapeutic target.

Abstract

Mixed lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the MLL gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of the transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with Lens Epithelium-Derived Growth Factor (LEDGF/p75; encoded by the PSIP1 gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL-fusion–mediated transformation and for the expression of downstream MLL-regulated genes like HOXA9 and MEIS1. In the light of developing a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional Psip1 knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. Psip1 knockout mice were viable but showed several defects in hematopoiesis, reduced colony-forming activity in vitro, decreased expression of Hox genes in the hematopoietic stem cells and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/p75 is dispensable for steady-state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of MLL-rearranged leukemia.

  • Submitted May 30, 2017.
  • Accepted October 20, 2017.