ESTABLISHMENT OF A HUMAN ACUTE PROMYELOCYTIC LEUKEMIA-ASCITES MODEL IN SCID MICE

Acute promyelocytic leukemia (APL) is an interesting model for cancer research because of the presence of the specific PML-RAR alpha fusion gene associated with the clinical response to retinoic acid differenti ation therapy. To better understand and improve differentiation induct ion with retinoic acid, we have established a human APL-ascites model in SCID mice using the NB4 human APL cell line. NB4 (1 x 10(6) cells) were transplanted into the peritoneum (IP) of SCID mice for 1 month. N B4 ascites cells (A-NB4) appeared, which were then engrafted in SCID m ice periodically for 18 passages at an interval of 3 to 4 weeks with a 100% success rate of tumor induction. The mean survival times of SCID mice transplanted with 1 x 10(6) A-NB4 cells was 21.6 +/- 2.3 days. A nalysis of the biologic characteristics of ninth passage NB4 ascitic c ells was performed and they were found to have the morphologic, immuno logic, cytogenetic, and molecular features of cultured NB4 cells. Furt hermore, A-NB4 cells were capable of differentiating when treated with all-trans retinoic acid (ATRA), as manifested by enhanced NBT reducti on and CD11b expression, In vivo treatment with ATRA in SCID mice for 4 days also increased NBT reduction by A-NB4 cells. ATRA treatment sig nificantly prolonged survival time in the group after transplantation (28.1 +/- 6.8 to 29.1 +/- 8.4 days) compared with the control (P < .00 1). Furthermore, treatment with adriamycin, an effective chemotherapeu tic drug in APL, had a strong growth suppressive effect on A-NB4 cells . These results demonstrate that this SCID-APL (NB4 ascites cells) mod el is a useful preclinical system for evaluating new or known drugs in the treatment of APL. (C) 1996 by The American Society of Hematology.