Integrin β5 and β7 expression in lenalidomide‐resistant multiple myeloma cells
Integrin β5 and β7 expression in lenalidomide‐resistant multiple myeloma cells
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来那度胺耐药多发性骨髓瘤细胞中整合素β5和β7的表达
DOI：
10.1007/s12185-022-03297-w
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发表时间：
2022
影响因子：
2.1
通讯作者：
Maki Hirao
中科院分区：
文献类型：
--
作者：
Yutaka Hattori;Takumi Futo;Ryo Uozaki;Daiju Ichikawa;Takashi Yamaguchi;Tomofumi Yamamoto;Maiko Matsushita;Maki Hirao
最近，Hosen N 等人。据报道，多发性骨髓瘤（MM）患者中活化的整合素β7频繁表达，但其临床意义尚不清楚[1]。他们还正在进行一项使用针对激活的整合素 β7 的 CAR-T 细胞疗法的临床试验 [1, 2]。在这里，我们报道了整合素β5和/或β7的表达与来那度胺耐药的关联。来那度胺在多发性骨髓瘤治疗中发挥了核心作用，但长期使用也导致了来那度胺耐药。尽管一些临床研究报告了 cereblon (CRBN) 下调或基因突变作为耐药机制，但其他分子机制尚未得到充分探索 [3]。为了解决这些问题，我们通过接触低剂量来那度胺建立了四种 MM 细胞系。如图1a所示，与亲代细胞相比，在KMS21R、MUM24R和KMS27R中观察到对来那度胺的敏感性显着降低。 KMS34R 细胞及其亲代 KMS34 细胞甚至对高浓度来那度胺都具有耐药性。此外，即使经过一个月的清除期，来那度胺耐药性也可能是不可逆转的（图S1）。还检查了对其他抗骨髓瘤药物的耐药性。 KMS21R、MUM24R 和 KMS34R 细胞往往比其亲代细胞对帕比司他更具耐药性（图 S2）。 MUM24R、KMS27R 和 KMS34R 细胞对硼替佐米也变得更加耐药。
Recently, Hosen N et al. reported frequent expression of activated integrin β7 in multiple myeloma (MM) patients though the clinical significance was not known [1]. They are also conducting a clinical trial using CAR-T-cell therapy targeting activated integrin β7 [1, 2]. Here we report association of expression of integrin β5 and/or β7 with lenalidomide resistance.Lenalidomide has played a central role in MM therapy, but long-term use has also led to lenalidomide-resistance. Although several clinical studies have reported down-regulation or genetic mutation of cereblon (CRBN) as a mechanism of resistance, other molecular mechanisms have not been fully explored [3]. To address these questions, we established four MM cell lines by exposure to low-dose lenalidomide. As shown in Fig. 1 a, a significant decrease in sensitivity to lenalidomide was observed in KMS21R, MUM24R and KMS27R compared with their parental cells. Both KMS34R cells and their parental KMS34 cells were resistant to even high-concentration lenalidomide. In addition, lenalidomide resistance is likely irreversible even after a month-long washout period (Fig. S1). Resistance to other anti-myeloma drugs was also examined. KMS21R, MUM24R and KMS34R cells tended to be more resistant to panobinostat than their parental cells (Fig. S2). MUM24R, KMS27R and KMS34R cells also became more resistant to bortezomib.