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RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia

Sylvia Snauwaert UGent, Stijn Vanhee UGent, Glenn Goetgeluk UGent, Greet Verstichel UGent, Yasmine Van Caeneghem UGent, Imke Velghe UGent, Jan Philippé UGent, Zwi N Berneman, Jean Plum UGent and Tom Taghon UGent, et al. (2012) HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. 97(10). p.1539-1547
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. Design and 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
leukemic stem cell, acute myeloid leukemia, cell therapy and immunotherapy, HMMR, RHAMM
journal title
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
Haematol-Hematol. J.
volume
97
issue
10
pages
1539 - 1547
Web of Science type
Article
Web of Science id
000310208400017
JCR category
HEMATOLOGY
JCR impact factor
5.935 (2012)
JCR rank
9/66 (2012)
JCR quartile
1 (2012)
ISSN
0390-6078
DOI
10.3324/haematol.2012.065581
language
English
UGent publication?
yes
classification
A1
additional info
TK and BV contributed equally to this manuscript as senior authors.
copyright statement
I have retained and own the full copyright for this publication
id
3033317
handle
http://hdl.handle.net/1854/LU-3033317
date created
2012-10-23 14:22:38
date last changed
2012-12-03 15:31:23
@article{3033317,
  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. 
Design and 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.},
  author       = {Snauwaert, Sylvia and Vanhee, Stijn and Goetgeluk, Glenn and Verstichel, Greet and Van Caeneghem, Yasmine and Velghe, Imke and Philipp{\'e}, Jan and Berneman, Zwi N and Plum, Jean and Taghon, Tom and Leclercq, Georges and Thielemans, Kris and Kerre, Tessa and Vandekerckhove, Bart},
  issn         = {0390-6078},
  journal      = {HAEMATOLOGICA-THE HEMATOLOGY JOURNAL},
  keyword      = {leukemic stem cell,acute myeloid leukemia,cell therapy and immunotherapy,HMMR,RHAMM},
  language     = {eng},
  number       = {10},
  pages        = {1539--1547},
  title        = {RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia},
  url          = {http://dx.doi.org/10.3324/haematol.2012.065581},
  volume       = {97},
  year         = {2012},
}

Chicago
Snauwaert, Sylvia, Stijn Vanhee, Glenn Goetgeluk, Greet Verstichel, Yasmine Van Caeneghem, Imke Velghe, Jan Philippé, et al. 2012. “RHAMM/HMMR (CD168) Is Not an Ideal Target Antigen for Immunotherapy of Acute Myeloid Leukemia.” Haematologica-the Hematology Journal 97 (10): 1539–1547.
APA
Snauwaert, S., Vanhee, S., Goetgeluk, G., Verstichel, G., Van Caeneghem, Y., Velghe, I., Philippé, J., et al. (2012). RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 97(10), 1539–1547.
Vancouver
1.
Snauwaert S, Vanhee S, Goetgeluk G, Verstichel G, Van Caeneghem Y, Velghe I, et al. RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. 2012;97(10):1539–47.
MLA
Snauwaert, Sylvia, Stijn Vanhee, Glenn Goetgeluk, et al. “RHAMM/HMMR (CD168) Is Not an Ideal Target Antigen for Immunotherapy of Acute Myeloid Leukemia.” HAEMATOLOGICA-THE HEMATOLOGY JOURNAL 97.10 (2012): 1539–1547. Print.