title: MLL-ENL leukemia burden initiated in femoral diaphysis and preceded by mature B-cell depletion.
abstract: BACKGROUND
  Molecular and cellular events that resulted in leukemia development are well characterized but initial engraftment and proliferation of leukemic cells in bone marrow and early modifications of the bone marrow microenvironment induced by engrafted leukemic cells remain to be clarified.
  
  
  METHODS
  After retro-orbital injection of 1,000 leukemic cells expressing Mixed Lineage Leukemia-Eleven Nineteen Leukemia fusion protein in non-conditioned syngenic mice, kinetics of leukemic burden and alterations of femoral hematopoietic populations were followed using an in vivo confocal imaging system and flow cytometry.
  
  
  RESULTS
  Three days after injection, 5% of leukemic cells were found in femurs. Little proliferation of engrafted leukemic cells could then be detected for more than two weeks while the number of femoral leukemic cells remained stable. Twenty days after injection, leukemic cells preferentially proliferated in femoral diaphysis where they formed clusters on the surface of blood vessels and bone. B220(+) lymphoid cells were found near these leukemic cell clusters and this association is correlated with a decreased number of femoral B220(+)IgM(+) cells. Increasing the number of injected leukemic cells or conditioning recipient mice with γ-irradiation resulted in leukemic cell development in diaphysis and knee. Competition experiments indicate that proliferation but not engraftment is a rate-limiting factor of leukemic cells spreading in diaphysis. Finally, 30 days after injection leukemia developed.
  
  
  CONCLUSIONS
  After retro-orbital injection of 1,000 leukemic cells expressing Mixed Lineage Leukemia-Eleven Nineteen Leukemia into syngenic mice, leukemic cell burden preferentially initiates in femoral diaphysis and is preceded by changes of femoral B-lymphoid populations.
authors.affiliation: CEA, iRCM, Laboratoire de recherche sur la, Réparation et la Transcription dans les cellules Souches, Fontenay-aux-Roses cedex, France.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jaracz-Ros
authors.forename: Daniel
authors.initials: D
authors.lastname: Lewandowski
authors.forename: Vilma
authors.initials: V
authors.lastname: Barroca
authors.forename: Catherine
authors.initials: C
authors.lastname: Lavau
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Roméo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018483:Diaphyses / Q000378:metabolism / Q000473:pathology; D005266:Femoral Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C493508:Mllt1 protein, mouse; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse