Targeting CD38 in acute myeloid leukemia interferes with leukemia trafficking and induces phagocytosis.
Targeting CD38 in acute myeloid leukemia interferes with leukemia trafficking and induces phagocytosis.
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DOI：
10.1038/s41598-021-01300-8
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发表时间：
2021-11-11
影响因子：
4.6
通讯作者：
Hanoun M
中科院分区：
文献类型：
--
作者：
Farber M;Chen Y;Arnold L;Möllmann M;Boog-Whiteside E;Lin YA;Reinhardt HC;Dührsen U;Hanoun M
靶向白血病细胞和微环境之间的相互作用是提高急性髓细胞白血病（AML）治疗效果的一种有吸引力的方法。AML浸润诱导人骨髓龛中炎性细胞因子的显著释放，其加速白血病发生。由于跨膜糖蛋白CD38已被证明可以调节细胞因子的释放，我们评估了在AML中抑制CD38的抗白血病潜力。AML细胞中的CD38表达被证明依赖于微环境线索，并且可以通过添加维甲酸来显著加强。事实上，抗CD38抗体达雷妥尤单抗在AML的3D体外三重培养模型中显示出显著的细胞生长抑制功效，但具有适度的细胞自主细胞毒性活性，且与CD38表达水平无关。与达雷妥尤单抗在AML中的主要微环境介导的活性一致，在异种移植模型中，CD38抑制显著诱导抗体依赖性吞噬作用，并干扰体内AML细胞运输，但总体上缺乏稳健的抗白血病作用。
Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML). AML infiltration induces a significant release of inflammatory cytokines in the human bone marrow niche which accelerates leukemogenesis. As the transmembrane glycoprotein CD38 has been shown to regulate cytokine release, we assessed the anti-leukemic potential of CD38 inhibition in AML. CD38 expression in AML cells proved to depend on microenvironmental cues and could be significantly enforced through addition of tretinoin. In fact, the anti-CD38 antibody daratumumab showed significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, but with modest cell-autonomous cytotoxic activity and independent of CD38 expression level. In line with a predominantly microenvironment-mediated activity of daratumumab in AML, CD38 inhibition significantly induced antibody-dependent phagocytosis and showed interference with AML cell trafficking in vivo in a xenograft transplantation model, but overall lacked robust anti-leukemic effects.
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影响因子：
20.3
作者：
Padró, T;Ruiz, S;Mesters, RM
通讯作者：
Mesters, RM
影响因子：
7.3
作者：
Piedra-Quintero ZL;Wilson Z;Nava P;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
23.9
作者：
Hanoun, Maher;Zhang, Dachuan;Mizoguchi, Toshihide;Pinho, Sandra;Pierce, Halley;Kunisaki, Yuya;Lacombe, Julie;Armstrong, Scott A.;Duehrsen, Ulrich;Frenette, Paul S.
通讯作者：
Frenette, Paul S.
影响因子：
11.2
作者：
Marlein, Christopher R.;Piddock, Rachel E.;Rushworth, Stuart A.
通讯作者：
Rushworth, Stuart A.
DOI：
10.1182/hematology.2019000045
发表时间：
2019-12-01
影响因子：
3
作者：
Leimkuhler, Nils B.;Schneider, Rebekka K.
通讯作者：
Schneider, Rebekka K.