PDF(Pubmed)
Abstract：
Essential thrombocythemia (ET) is one of the most common types of Ph-negative myeloproliferative neoplasms, an infrequent group of blood cancers that arise from a CD34 + hematopoietic stem cell (HSC) in the bone marrow (BM) primarily due to driver mutations in JAK2, CALR or MPL. These aberrations result in an overproduction of mature myeloid cells in peripheral blood (PB). To date, no targeted therapies have been approved for ET patients, so the study of the molecular mechanisms behind the disease and the identification of new therapeutic targets may be of interest. For this reason, in this study, we have compared the transcriptomic profile of undifferentiated CD34 + cells and mature myeloid cells from ET patients (CALR and JAK2-mutated) and healthy donors deposited in publicly available databases. The study of the similarities and differences between these samples might help to better understand the molecular mechanisms behind the disease according to the degree of maturation of the malignant clone and the type of mutation and ultimately help identify new therapeutic targets for these patients.
The results show that most of the altered hallmarks in neutrophils were also found in CD34 + cells. However, only a few genes showed a similar aberrant expression pattern in both types of cells. We have identified a signature of six genes common to patients with CALR and JAK2 mutations (BPI, CRISP3, LTF, MMP8, and PTGS1 upregulated, and PBXIP1 downregulated), a different signature of seven genes for patients with CALR mutations (BMP6, CEACAM8, ITK, LCN2, and PRG2 upregulated, and MAN1A1 and MME downregulated) and a signature of 13 genes for patients with JAK2 mutations (ARG1, CAST, CD177, CLEC5A, DAPP1, EPS15, IL18RAP, OLFM4, OLR1, RIOK3, SELP, and THBS1 upregulated, and IGHM downregulated).
Our results highlight transcriptomic similarities and differences in ET patients according to the degree of maturation of the malignant clone and the type of mutation. The genes and processes altered in both CD34 + cells and mature neutrophils may reveal altered sustained processes that could be studied as future therapeutic targets for ET patients.
The results show that most of the altered hallmarks in neutrophils were also found in CD34 + cells. However, only a few genes showed a similar aberrant expression pattern in both types of cells. We have identified a signature of six genes common to patients with CALR and JAK2 mutations (BPI, CRISP3, LTF, MMP8, and PTGS1 upregulated, and PBXIP1 downregulated), a different signature of seven genes for patients with CALR mutations (BMP6, CEACAM8, ITK, LCN2, and PRG2 upregulated, and MAN1A1 and MME downregulated) and a signature of 13 genes for patients with JAK2 mutations (ARG1, CAST, CD177, CLEC5A, DAPP1, EPS15, IL18RAP, OLFM4, OLR1, RIOK3, SELP, and THBS1 upregulated, and IGHM downregulated).
Our results highlight transcriptomic similarities and differences in ET patients according to the degree of maturation of the malignant clone and the type of mutation. The genes and processes altered in both CD34 + cells and mature neutrophils may reveal altered sustained processes that could be studied as future therapeutic targets for ET patients.
摘要：
背景：原发性血小板增多症（ET）是Ph阴性骨髓增殖性肿瘤的最常见类型之一，一组罕见的血液癌症，主要是由于JAK2，CALR或MPL的驱动突变引起的骨髓（BM）中的CD34造血干细胞（HSC）。这些畸变导致外周血(PB)中成熟骨髓细胞的过量产生。迄今为止,尚未批准针对ET患者的靶向治疗，因此，对疾病背后的分子机制的研究和新的治疗靶点的识别可能是有意义的。出于这个原因,在这项研究中，我们比较了公开数据库中保存的ET患者(CALR和JAK2突变)和健康供体的未分化CD34+细胞和成熟骨髓细胞的转录组学谱.根据恶性克隆的成熟程度和突变类型，研究这些样本之间的异同可能有助于更好地了解疾病背后的分子机制，并最终帮助确定这些患者的新治疗靶标。
结果：结果表明，中性粒细胞中的大部分改变标志也在CD34+细胞中发现。然而,只有少数基因在两种类型的细胞中显示出相似的异常表达模式。我们已经确定了CALR和JAK2突变患者常见的六个基因的特征（BPI，CRISP3,LTF,MMP8和PTGS1上调,和PBXIP1下调)，CALR突变患者的七个基因的不同特征(BMP6，CEACAM8，ITK，LCN2和PRG2上调，和MAN1A1和MME下调）以及JAK2突变患者的13个基因的签名（ARG1，CAST，CD177,CLEC5A,DAPP1,EPS15,IL18RAP,OLFM4,OLR1,RIOK3,SELP,和THBS1上调，和IGHM下调)。
结论：我们的结果根据恶性克隆的成熟程度和突变类型强调了ET患者转录组的相似性和差异。CD34+细胞和成熟中性粒细胞中改变的基因和过程可能揭示了改变的持续过程，可以作为ET患者的未来治疗靶标进行研究。
结果：结果表明，中性粒细胞中的大部分改变标志也在CD34+细胞中发现。然而,只有少数基因在两种类型的细胞中显示出相似的异常表达模式。我们已经确定了CALR和JAK2突变患者常见的六个基因的特征（BPI，CRISP3,LTF,MMP8和PTGS1上调,和PBXIP1下调)，CALR突变患者的七个基因的不同特征(BMP6，CEACAM8，ITK，LCN2和PRG2上调，和MAN1A1和MME下调）以及JAK2突变患者的13个基因的签名（ARG1，CAST，CD177,CLEC5A,DAPP1,EPS15,IL18RAP,OLFM4,OLR1,RIOK3,SELP,和THBS1上调，和IGHM下调)。
结论：我们的结果根据恶性克隆的成熟程度和突变类型强调了ET患者转录组的相似性和差异。CD34+细胞和成熟中性粒细胞中改变的基因和过程可能揭示了改变的持续过程，可以作为ET患者的未来治疗靶标进行研究。
