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

(2018) BLOOD. 131(1). p.95-107
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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 such as HOXA9 and MEIS1. In 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.
Keywords
MIXED-LINEAGE LEUKEMIA, GROWTH-FACTOR LEDGF/P75, BONE-MARROW-CELLS, FUSION PROTEINS, DIFFERENTIAL EXPRESSION, THERAPEUTIC TARGET, HOMEOBOX, GENES, MENIN, INHIBITION, INTEGRATION

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Chicago
El Ashkar, Sara, Juerg Schwaller, Tim Pieters, Steven Goossens, Jonas Demeulemeester, Frauke Christ, Siska Van Belle, et al. 2018. “LEDGF/p75 Is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis.” Blood 131 (1): 95–107.
APA
El Ashkar, S., Schwaller, J., Pieters, T., Goossens, S., Demeulemeester, J., Christ, F., Van Belle, S., et al. (2018). LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. BLOOD, 131(1), 95–107.
Vancouver
1.
El Ashkar S, Schwaller J, Pieters T, Goossens S, Demeulemeester J, Christ F, et al. LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. BLOOD. 2018;131(1):95–107.
MLA
El Ashkar, Sara, Juerg Schwaller, Tim Pieters, et al. “LEDGF/p75 Is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis.” BLOOD 131.1 (2018): 95–107. Print.
@article{8556075,
  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 such as HOXA9 and MEIS1. In 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.},
  author       = {El Ashkar, Sara and Schwaller, Juerg and Pieters, Tim and Goossens, Steven and Demeulemeester, Jonas and Christ, Frauke and Van Belle, Siska and Juge, Sabine and Boeckx, Nancy and Engelman, Alan and Van Vlierberghe, Pieter and Debyser, Zeger and De Rijck, Jan},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {MIXED-LINEAGE LEUKEMIA,GROWTH-FACTOR LEDGF/P75,BONE-MARROW-CELLS,FUSION PROTEINS,DIFFERENTIAL EXPRESSION,THERAPEUTIC TARGET,HOMEOBOX,GENES,MENIN,INHIBITION,INTEGRATION},
  language     = {eng},
  number       = {1},
  pages        = {95--107},
  title        = {LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis},
  url          = {http://dx.doi.org/10.1182/blood-2017-05-786962},
  volume       = {131},
  year         = {2018},
}

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