Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate school of Medicine, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan.
Leuk Res. 2022 Aug;119:106883. doi: 10.1016/j.leukres.2022.106883. Epub 2022 May 31.
Cyclic AMP-response element-binding protein 3-like 1 (CREB3L1) is a gene involved in the unfolded protein response (UPR). Recently, we demonstrated that CREB3L1 is specifically overexpressed in the platelets of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In this study, we aimed to show the clinical and biological relevance of CREB3L1 in these hematological diseases. Overexpression of CREB3L1 was specific to platelets in MPNs and associated with a higher risk of thrombosis and fibrotic transformation in essential thrombocythemia (ET) and polycythemia vera (PV) cases, respectively. Furthermore, we found that UPR genes were downregulated in platelets of patients with ET and PV, which were more pronounced in patients harboring the JAK2 V617F mutation. However, CREB3L1 overexpression does not alter UPR gene expression or cell proliferation in UT-7/TPO/CALRm cells exogenously expressing mutated calreticulin and HEL cells harboring endogenous JAK2 V617F. Furthermore, CREB3L1 overexpression did not modulate sensitivity to endoplasmic reticulum stress in these cell lines. Taken together, our data show 1) a potential role of CREB3L1 expression in platelets as a new marker of high-risk MPNs and 2) an association between CREB3L1 overexpression and UPR gene downregulation in these patients' platelets, with CREB3L1 not altering UPR in our in vitro models and possibly further in vivo mechanisms being involved.
环磷酸腺苷反应元件结合蛋白 3 样 1（CREB3L1）是参与未折叠蛋白反应（UPR）的基因。最近，我们证明 CREB3L1 在费城染色体阴性骨髓增殖性肿瘤（MPN）患者的血小板中特异性过表达。在这项研究中，我们旨在展示 CREB3L1 在这些血液疾病中的临床和生物学相关性。在 MPN 中，CREB3L1 的过表达特异性存在于血小板中，分别与原发性血小板增多症（ET）和真性红细胞增多症（PV）病例中的血栓形成和纤维化转化风险增加相关。此外，我们发现 ET 和 PV 患者的血小板中 UPR 基因下调，在携带 JAK2 V617F 突变的患者中更为明显。然而，CREB3L1 的过表达不会改变外源性表达突变钙网蛋白的 UT-7/TPO/CALRm 细胞和内源性携带 JAK2 V617F 的 HEL 细胞中 UPR 基因的表达或细胞增殖。此外，CREB3L1 的过表达不会调节这些细胞系对内质网应激的敏感性。总之，我们的数据表明 1）CREB3L1 在血小板中的表达可能作为高危 MPN 的新标志物，以及 2）在这些患者的血小板中 CREB3L1 过表达与 UPR 基因下调之间的关联，而 CREB3L1 在我们的体外模型中并未改变 UPR，可能涉及进一步的体内机制。
