Morten Orebo Holmström, Josephine Hallundbæk Ruders, Caroline Hasselbalch Riley, Morten Kranker Larsen, Jacob Handlos Grauslund, Lasse Kjær, Vibe Skov, Christina Ellervik, Belinda B Guo, Matthew Linden, Hans Carl Hasselbalch, Mads Hald Andersen
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We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. 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引用次数: 0
摘要
最近,一种可抑制糖蛋白 A 重复优势(GARP)介导的活性转化生长因子β(TGFβ)从 TGFβ 前肽潜伏相关肽(LAP)中释放的抗体在慢性骨髓增生性肿瘤(MPN)小鼠模型中显示出临床前活性。因此,我们研究了 56 名 MPN 患者和 11 名健康供体(HD)的外周血淋巴细胞中免疫抑制分子 LAP 和 GARP 的表达情况。我们发现,MPN 患者的淋巴细胞表达较高水平的 LAP 和 GARP,而不同 MPN 诊断之间并无明显差异。临床参数对淋巴细胞表达 LAP 和 GARP 的影响表明,与 HD 和 Januskinase2(JAK2)突变患者相比,钙调蛋白(CALR)突变 MPN 患者的淋巴细胞表达更高。与活化血小板结合的淋巴细胞比例(aPLT)与 LAP 和 GARP 的表达密切相关,这表明 MPN 患者淋巴细胞上 GARP 和 LAP 表达增加的原因不是淋巴细胞本身,而是 aPLT。值得注意的是,JAK2-患者和 CALRmut 患者的血小板计数和抗血栓治疗均无差异。血小板基因表达分析未能发现 JAK2- 和 CALRmut 患者的相关基因表达存在差异。
The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.
Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients.
期刊介绍:
The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.