Tracking the extramedullary PML-RARα-positive cell reservoirs in a preclinical model: biomarker of long-term drug efficacy.
Using an acute promyelocytic leukemia (APL) preclinical model, we show that oncogene-specific PCR (Polymerase Chain Reaction)-based assays allow to evaluate the efficacy of immunotherapy combining all-trans retinoic acid (ATRA) and a DNA-based vaccine targeting the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) oncogene. Kaplan-Meier survival analysis according to the peripheral blood PML-RARα normalized copy number (NCN) clearly shows that ATRA + DNA-treated mice with an NCN lower than 10 (43%) formed the group with a highly significant (p < 0.0001) survival advantage. Furthermore, a PCR assay was used to assess various tissues and organs for the presence of PML-RARα-positive cells in long-term survivors (n = 15). As expected, the majority of mice (n = 10) had no measurable tissue level of PML-RARα. However, five mice showed a weak positive signal in both the brain and spleen (n = 2), in the brain only (n = 2) and in the spleen only (n = 1). Thus tracking the oncogene-positive cells in long-term survivors reveals for the first time that extramedullary PML-RARα-positive cell reservoirs such as the brain may persist and be involved in relapses.
INSERM U940, F-75475 Paris, France.
Katerina
K
Pokorna
Carole
C
Le Pogam
Martine
M
Chopin
Nicole
N
Balitrand
Murielle
M
Reboul
Bruno
B
Cassinat
Christine
C
Chomienne
Rose Ann
RA
Padua
Marika
M
Pla
D000818:Animals; D001921:Brain / Q000166:cytology; D018628:Gene Dosage; D007167:Immunotherapy; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*; D019444:Vaccines, DNA / Q000627:therapeutic use*
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019444:Vaccines, DNA; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin