title: The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion.
abstract: Fanconi anemia (FA) is an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca-/-hematopoietic stem cells to DNA crosslinking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of pre-leukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability, but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients. Furthermore, we identified transcription program underlying dysregulated DDR and cell migration, myeloid proliferation, and immune response in the Fanca-/-pre-LSCs. Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca-/-pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca-/-pre-LSC expansion and leukemia development. Our study implicates diminishing DDR as a root cause of FA leukemogenesis, which subsequently collaborates with other signaling pathways for leukemogenic transformation.
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Divisions of Radiation Health, Department of Pharmaceutical Science, College of Pharmacy, UAMS, Little Rock, AR, USA.
authors: W
authors: 0000-0003-3669-537X
authors: W
authors: Du
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: S
authors: S
authors: Amarachintha
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: A
authors: A
authors: Wilson
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Q
authors: Q
authors: Pang
mesh_terms: D000818:Animals; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D005838:Genotype; D056747:Immunomodulation / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011289:Preleukemia / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D015415:Biomarkers; D052217:Fanconi Anemia Complementation Group A Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1