Tracking the extramedullary PML-RARα-positive cell reservoirs in a preclinical model: Biomarker of long-term drug efficacy

• Published in: Molecular and cellular probes Vol. 27; no. 1; pp. 1 - 5
• Main Authors: Pokorna, Katerina, Le Pogam, Carole, Chopin, Martine, Balitrand, Nicole, Reboul, Murielle, Cassinat, Bruno, Chomienne, Christine, Padua, Rose Ann, Pla, Marika
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2013
• Subjects: Animal model; Animals; APL; ATRA; Brain - cytology; Gene Dosage; Immunotherapy; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute - mortality; Leukemia, Promyelocytic, Acute - therapy; Mice; Mice, Transgenic; MRD; Neoplasm Proteins - therapeutic use; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - immunology; Oncogene Proteins, Fusion - metabolism; RT-qPCR; Spleen - cytology; Treatment Outcome; Tretinoin - therapeutic use; Vaccination; Vaccines, DNA - therapeutic use; Animal model; ATRA; APL; RT-qPCR; Vaccination; MRD
• ISSN: 0890-8508; 1096-1194
• DOI: 10.1016/j.mcp.2012.08.001

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.