Dubois C, Schlageter M H, de Gentile A, Balitrand N, Toubert M E, Krawice I, Fenaux P, Castaigne S, Najean Y, Degos L
Laoratoire de Biologie, Cellulaire Hématopoïétique, Institut d'Hématologie, Hopital Saint Louis, Paris, France.
Leukemia. 1994 Oct;8(10):1750-7.
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 retinoic acid (ATRA) differentiating effect. We have recently reported that 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 drawbacks is the increase of peripheral blast cells often associated with the ATRA leukocyte activation syndrome. To determine if this specific side-effect was linked to an increase of HGF release by APL cells, we studied the modulation of cytokine production by APL cells, we studied the modulation of cytokine production by APL samples (n = 12) before 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 non-APL cells (n = 8). Interestingly, the increase of IL-1 beta and G-CSF production in the presence of ATRA was highly correlated to an increase in APL cell count in vitro and in vivo hyperleukocytosis, resulting 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 suggest that ATRA-induced hyperleukocytosis and ATRA leukocyte activation syndrome in APL may be inherent to the secretion of specific hematopoietic growth factors by the APL cells.
急性早幼粒细胞白血病（APL）是急性髓系白血病（AML）的一个同质性亚组，其特征为存在t(15;17)易位及由此产生的PML/RARα融合蛋白。迄今为止，APL是唯一对全反式维甲酸（ATRA）的分化作用足够敏感的AML。我们最近报道，APL表达并分泌造血生长因子（HGF），如白细胞介素-1β（IL-1β）、肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）。在体内，单独使用ATRA可使APL患者实现完全缓解。ATRA治疗的缺点之一是外周原始细胞增多，这通常与ATRA白细胞激活综合征相关。为了确定这种特定的副作用是否与APL细胞释放HGF增加有关，我们研究了APL细胞对细胞因子产生的调节，我们研究了12例APL样本在与ATRA孵育前后细胞因子产生的调节情况。ATRA未能调节TNFα、IL-6或粒细胞-巨噬细胞集落刺激因子（GM-CSF）分泌水平；然而，11例患者的IL-8水平下降，4例患者观察到IL-1β和粒细胞集落刺激因子（G-CSF）蛋白表达上调。这些调节被发现与ATRA敏感性有关，因为ATRA未能调节非APL细胞（8例）的细胞因子产生。有趣的是，在ATRA存在的情况下，IL-1β和G-CSF产生的增加与体外APL细胞计数增加和体内白细胞增多高度相关，导致致命后果。已知IL-1β、TNFα、IL-6和IL-8与白细胞激活有关。本研究结果表明，APL中ATRA诱导的白细胞增多和ATRA白细胞激活综合征可能是APL细胞分泌特定造血生长因子所固有的。
