Institute of Blood and Marrow Transplantation, National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou Medical College, Soochow University, Suzhou, China.
Key Lab of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Medical College, Soochow University, Suzhou, China.
Exp Hematol. 2023 Sep-Oct;125-126:45-54. doi: 10.1016/j.exphem.2023.07.001. Epub 2023 Jul 5.
The biology of the matrix remodeling-associated 7 (MXRA7) gene has been ill defined. Bioinformatic analysis of public data sets revealed that MXRA7 messenger RNA (mRNA) was highly expressed in acute myeloid leukemia (AML), especially acute promyelocytic leukemia (APL). High expression of MXRA7 was associated with poor overall survival of patients with AML. We confirmed that MXRA7 expression was upregulated in patients with APL and cell lines. Knockdown or overexpression of MXRA7 did not affect the proliferation of NB4 cells directly. Knockdown of MXRA7 in NB4 cells promoted drug-induced cell apoptosis, whereas overexpression of MXRA7 had no obvious influence on drug-induced cell apoptosis. Lowering MXRA7 protein levels in NB4 cells promoted all-trans retinoic acid (ATRA)-induced cell differentiation possibly through decreasing the PML-RARα level and increasing PML and RARα levels. Correspondingly, overexpression of MXRA7 showed consistent results. We also demonstrated that MXRA7 altered the expression of genes involved in leukemic cell differentiation and growth. Knockdown of MXRA7 upregulated the expression levels of C/EBPB, C/EBPD, and UBE2L6, and downregulated the expression levels of KDM5A, CCND2, and SPARC. Moreover, knockdown of MXRA7 inhibited the malignancy of NB4 cells in a non-obese diabetic-severe combined immune-deficient mice model. In conclusion, this study demonstrated that MXRA7 influences the pathogenesis of APL via regulation of cell differentiation. The novel findings about the role of MXRA7 in leukemia not only shed light on the biology of this gene but also proposed this gene as a new target for APL treatment.
基质重塑相关 7（MXRA7）基因的生物学特性尚未明确。对公共数据集的生物信息学分析显示，MXRA7 信使 RNA（mRNA）在急性髓系白血病（AML）中高度表达，尤其是急性早幼粒细胞白血病（APL）。MXRA7 高表达与 AML 患者总生存期不良相关。我们证实，APL 患者和细胞系中 MXRA7 的表达上调。MXRA7 的敲低或过表达并未直接影响 NB4 细胞的增殖。NB4 细胞中 MXRA7 的敲低促进了药物诱导的细胞凋亡，而过表达 MXRA7 对药物诱导的细胞凋亡没有明显影响。NB4 细胞中 MXRA7 蛋白水平的降低可能通过降低 PML-RARα 水平和增加 PML 和 RARα 水平，促进全反式维甲酸（ATRA）诱导的细胞分化。相应地，过表达 MXRA7 也显示出一致的结果。我们还表明，MXRA7 改变了参与白血病细胞分化和生长的基因的表达。MXRA7 的敲低上调了 C/EBPB、C/EBPD 和 UBE2L6 的表达水平，下调了 KDM5A、CCND2 和 SPARC 的表达水平。此外，MXRA7 的敲低抑制了 NB4 细胞在非肥胖型糖尿病-严重联合免疫缺陷小鼠模型中的恶性肿瘤形成。总之，本研究表明，MXRA7 通过调节细胞分化影响 APL 的发病机制。关于 MXRA7 在白血病中的作用的新发现不仅阐明了该基因的生物学特性，还提出了该基因作为 APL 治疗的新靶点。
