title: RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia.
abstract: BACKGROUND
  Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored.
  
  
  METHODS
  Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation.
  
  
  RESULTS
  High levels of RHAMM were expressed by CD34(+)CD38(+) and CD34(-) acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34(+)CD38(-) leukemic stem cells, and was not different from that in CD34(+)CD38(-) hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34(+) cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells.
  
  
  CONCLUSIONS
  RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Snauwaert
authors.forename: Stijn
authors.initials: S
authors.lastname: Vanhee
authors.forename: Glenn
authors.initials: G
authors.lastname: Goetgeluk
authors.forename: Greet
authors.initials: G
authors.lastname: Verstichel
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Van Caeneghem
authors.forename: Imke
authors.initials: I
authors.lastname: Velghe
authors.forename: Jan
authors.initials: J
authors.lastname: Philippé
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Tessa
authors.initials: T
authors.lastname: Kerre
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016130:Immunophenotyping; D007167:Immunotherapy; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor