Brenner Annette K, Tvedt Tor Henrik Anderson, Nepstad Ina, Rye Kristin P, Hagen Karen M, Reikvam Håkon, Bruserud Øystein
a Section for Haematology, Department of Clinical Science , University of Bergen , Bergen , Norway.
b Department of Medicine , Haukeland University Hospital , Bergen , Norway.
Expert Opin Ther Targets. 2017 Apr;21(4):357-369. doi: 10.1080/14728222.2017.1300255. Epub 2017 Mar 3.
Acute myeloid leukaemia (AML) is a heterogeneous malignancy; we studied how the constitutive cytokine release by the AML cells varies among patients.
We investigated the constitutive release of 28 mediators during in vitro culture for 79 consecutive patients.
Constitutive cytokine release profiles differed among patients, and hierarchical clustering identified three subsets with high, intermediate and low release, respectively. The high-release subset showed high levels of most mediators, usually monocytic differentiation as well as altered mRNA expression of proteins involved in intracellular iron homeostasis and molecular trafficking; this subset also included 4 out of 6 patients with inv(16). Spontaneous in vitro apoptosis did not differ among the subsets. For the high-release patients, cytokines were released both by CD34 and CD34 cells. The mRNA and released protein levels showed statistically significant correlations only for eleven of the cytokines. The overall survival after intensive anti-leukemic therapy was significantly higher for high-release compared with low-release patients. Pharmacological targeting of iron metabolism (iron chelation, transferrin receptor blocking) altered the cytokine release profile.
Subclassification of AML patients based on the constitutive cytokine release may be clinically relevant and a part of a low-risk (i.e. chemosensitive) AML cell phenotype.
急性髓系白血病（AML）是一种异质性恶性肿瘤；我们研究了AML细胞组成性细胞因子释放情况在患者之间的差异。
我们调查了79例连续患者在体外培养7天期间28种介质的组成性释放情况。
患者之间的组成性细胞因子释放谱不同，层次聚类分别识别出高释放、中释放和低释放三个亚组。高释放亚组显示大多数介质水平较高，通常具有单核细胞分化以及参与细胞内铁稳态和分子运输的蛋白质的mRNA表达改变；该亚组还包括6例inv(16)患者中的4例。各亚组之间的体外自发凋亡无差异。对于高释放患者，细胞因子由CD34⁺和CD34⁻细胞释放。mRNA和释放的蛋白质水平仅在11种细胞因子中显示出统计学上的显著相关性。与低释放患者相比，高释放患者在强化抗白血病治疗后的总生存率显著更高。铁代谢的药物靶向治疗（铁螯合、转铁蛋白受体阻断）改变了细胞因子释放谱。
基于组成性细胞因子释放对AML患者进行亚分类可能具有临床相关性，并且是低风险（即化疗敏感）AML细胞表型的一部分。
