title: c-Met inhibition in a HOXA9/Meis1 model of CN-AML.
abstract: BACKGROUND
  Hematopoiesis is a paradigm for developmental processes, hierarchically organized, with stem cells at its origin. Hematopoietic stem cells (HSCs) replenish progenitor and precursor cells of multiple lineages, which normally differentiate into short-lived mature circulating cells. Hematopoiesis has provided insight into the molecular basis of tissue homeostasis and malignancy. Malignant hematopoiesis, in particular acute myeloid leukemia (AML), results from impaired development or differentiation of HSCs and progenitors. Co-overexpression of HOX and TALE genes, particularly the HOXA cluster and MEIS1, is associated with AML. Clinically relevant models of AML are required to advance drug development for an aging patient cohort.
  
  
  RESULTS
  Molecular analysis identified altered gene, microRNA, and protein expression in HOXA9/Meis1 leukemic bone marrow compared to normal controls. A candidate drug screen identified the c-Met inhibitor SU11274 for further analysis. Altered cell cycle status, apoptosis, differentiation, and impaired colony formation were shown for SU11274 in AML cell lines and primary leukemic bone marrow.
  
  
  CONCLUSIONS
  The clonal HOXA9/Meis1 AML model is amenable to drug screening analysis. The data presented indicate that human AML cells respond in a similar manner to the HOXA9/Meis1 cells, indicating pre-clinical relevance of the mouse model.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: Nuala M
authors.initials: NM
authors.lastname: Mulgrew
authors.forename: Laura M J
authors.initials: LM
authors.lastname: Kettyle
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Ramsey
authors.forename: Susan
authors.initials: S
authors.lastname: Cull
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Smyth
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Mervyn
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Bijl
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D018398:Homeodomain Proteins; D007211:Indoles; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D010879:Piperazines; D013449:Sulfonamides; C097899:homeobox protein HOXA9; D019859:Proto-Oncogene Proteins c-met
keywords: HOXA9; Meis1; candidate drugs; leukemia; mouse model