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Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

机译:jak2的经常性数值像差和淋巴瘤jak2-sats cascade的放松管制

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The Janus kinase 2 (JAK2)-signal transducers and activators of transcription (STAT) pathway plays an important role in hematological malignancies. Mutations and translocations of the JAK2 gene, mapped at 9p24, lead to constitutive activation of JAK2 and its downstream targets. The presence of JAK2 mutations in lymphomas has been addressed in larger cohorts, but there are little systemic data on numerical and structural JAK2 aberrations in lymphoid neoplasms. To study the molecular epidemiology of these aberrations and the consecutive activation of the JAK2-STAT pathway in lymphomas, we examined 527 cases, covering the most common entities, in a tissue microarray by fluorescent in situ hybridization with breakable JAK2 probes, and immunohistochemistry for phosphorylated JAK2 (pJAK2) and its preferred downstream pSTAT3 and pSTAT5. 9p24 gains were detected in 6/17 (35%) primary mediastinal B-cell lymphomas (PMBCLs), 25/77 (33%) Hodgkin's lymphomas (HLs), 3/16 (19%) angioimmunoblastic T-cell lymphomas (AILTs) and 1/5 ALK1+ anaplastic large cell lymphomas (ALCLs); breaks were observed only in three cases. pJAK2 expression was most prevalent in PMBCL, peripheral T-cell lymphomas and HL. pSTAT3 predominated in ALCLs, HLs, AILTs, PMBCLs and peripheral T-cell lymphomas. pSTAT5 expression was detected frequently in follicular lymphomas, diffuse large B-cell lymphomas and AILTs. 9p24 gains correlated with increased proportions of tumor cells expressing pJAK2 (P=0.002) and pSTAT3 (P=0.001). In follicular lymphomas, concomitant expression of pJAK2 and pSTAT5 was linked to better prognosis, whereas expression of pSTAT3 in nongerminal center-like diffuse large B-cell lymphomas could identify a patient group with an inferior outcome. Our findings stress that despite the rarity of activating JAK2 mutations in lymphomas, JAK2 is recurrently targeted by numerical, and rarely by structural, genetic aberrations in distinct lymphoma subtypes and that JAK2-STAT pathway may play a role in lymphomagenesis.
机译:Janus激酶2(JAK2) - 转录(统计学)途径(统计)途径的激活剂在血液恶性肿瘤中起着重要作用。 JAK2基因的突变和旋转映射在9p24,导致JAK2及其下游靶的组成型激活。在较大的队列中已经解决了淋巴瘤中JAK2突变的存在,但在淋巴肿瘤中存在关于数值和结构JAK2像差的全身数据。为了研究这些像差的分子流行病学和淋巴瘤中JAK2-STAT途径的连续激活,我们检查了527例,覆盖了最常见的实体,在组织微阵列中,通过荧光与可易碎的JAK2探针杂交,以及用于磷酸化的免疫组织化学JAK2(PJAK2)及其首选下游PSTAT3和PSTAT5。在6/17(35 %)原发性纵隔B细胞淋巴瘤(PMBCLS),25/77(33 %)Hodgkin的淋巴瘤(HLS),3/16(19 %)血管免疫细胞淋巴瘤中,检测到9p24 (疾病)和1/5 Alk1 + Anpluplastic大细胞淋巴瘤(ALCL);只在三种情况下观察到休息。 PJAK2表达在PMBCL,外周T细胞淋巴瘤和HL中最普遍。 PSTAT3以ALCLS,HLS,AILTS,PMBCLS和外周T细胞淋巴瘤占优势。在滤泡淋巴瘤中经常检测到PSTAT5表达,弥漫性大B细胞淋巴瘤和肥胖。 9P24增益与表达PJAK2的肿瘤细胞的比例增加(p = 0.002)和Pstat3(p = 0.001)。在滤泡淋巴瘤中,PJAK2和PSTAT5的伴随表达与更好的预后相关,而Pstat3在非正恒中心的漫射大B细胞淋巴瘤中的表达可以鉴定具有较差结果的患者组。我们的研究结果强调认为,尽管在淋巴瘤中激活JAK2突变,但JAK2通过数值靶向,并且很少通过不同的淋巴瘤亚型中的结构遗传畸变,并且JAK2-STAT途径可能在淋巴瘤中发挥作用。

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