MODULATION OF IL-8, IL-1-BETA, AND G-CSF SECRETION BY ALL-TRANS-RETINOIC ACID IN ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of the t(15;17) translocation and the resulting PML/RAR alpha fusion proteins. To date APL is the only AML which is sufficiently sensitive to all-trans reti noic acid's (ATRA) differentiating effect. We have recently reported t hat APL express and secrete hematopoietic growth factors (HGF) such as IL-1 beta, TNF alpha, and IL-6. In vivo ATRA alone allows achievement of complete remission in APL patients. One of ATRA therapy's draw-bac ks is the increase of peripheral blast cells often associated with the ATRA leukocyte activation syndrome. To determine if this specific sid e-effect was linked to an increase of HGF release by APL cells, we stu died the modulation of cytokine production by APL samples (n = 12) bef ore and after incubation with ATRA. ATRA failed to modulate TNF alpha, IL-6 or GM-CSF secretion levels; however, IL-8 levels decreased in 11 cases, and in four cases up-regulation of IL-1 beta and G-CSF protein expression was observed. These modulations were found to be linked to ATRA sensitivity as ATRA failed to modulate cytokine production in no n-APL cells (n = 8). Interestingly, the increase of IL-1 beta and G-CS F production in the presence of ATRA was highly correlated to an incre ase in APL cell count in vitro and in vivo hyperleukocytosis, resultin g in fatal outcome. IL-1 beta, TNF alpha, IL-6, and IL-8 are known to be implicated in leukocyte activation. The results of this study sugge st that ATRA-induced hyperleukocytosis and ATRA leukocyte activation s yndrome in APL may be inherent to the secretion of specific hematopoie tic growth factors by the APL cells.