大颗粒淋巴细胞白血病和JAK/STAT信号通路

Large Granular Lymphocytic Leukemia and JAK/STAT Signaling Pathway

大颗粒淋巴细胞白血病(large granular lymphocytic leukemia,LGLL)是一类少见的淋巴增殖性疾病,是血液和骨髓中细胞毒性T细胞和NK细胞的克隆性扩增,常常和自身免疫性疾病有关。根据2008年WHO淋巴与造血组织肿瘤分类,LGLL分为T细胞大颗粒淋巴细胞白血病(Tell large granular lymphocytic leukemia T-,GLL)、慢性NK细胞增殖性疾病(chronic lymphoproliferative disease of NK cells,CLPD-VK)和侵袭性NK细胞白血病(aggressive NK cell leukemia,ANKL)。由于对这种疾病缺乏认识,一些患者可能被误诊或者漏诊。目前,LGLL的发病机制尚不清楚,并且治疗效果并不令人满意。因此发现这种疾病的预后标记和治疗靶点十分必要。JAK/STAT通路的持续激活与LGLL的发展密切相关,近年来,在LGLL中发现STAT3基因的突变,突变位于二聚化界面上的SH2区域,介导STAT3的激活。STAT3是第1个针对LGLL高度特异的分子标记,在其他肿瘤中几乎检测不到STAT3的突变。因此,STAT3突变能被用作为LGLL诊断的分子标记,并为LGLL提供一个新的治疗靶点。

Large granular lymphocytic leukemia(LGLL) is a rare lymphoproliferative disorder of clonal expansion of cytotoxic T-or NK-cells in blood and bone marrow,and often associated with autoimmune disorders.According to the current WHO classification of the hematopoietic and lymphoid tissue tumors,the clonal LGL expansions are further classified as T-cell large granular lymphocytic leukemia(T-LGLL),chronic lymphoproliferative disorders of NK cells(CLPD-NK) and aggressive NK cell leukemia.Since there is a general lack of awareness of this disease,some patients may be misdiagnosed or some cases may be missed when diagnosis was done.At present,the pathogenesis of LGLL remains incomplete and unclear,and the therapeutic effects are unsatisfactory.For this reason,it is necessary to find prognostic marks and therapeutic targets of this disease.The constitutive activation of JAK/STAT pathway has been claimed to be involved in the development of LGLL.Recently,the somatic mutations in the SH2 domain of STAT3 in LGLL are frequently observed,which lead to the activation of JAK/STAT pathway.STAT3 is the first molecular markers that are highly specific for LGLL,and STAT3 mutations have been rarely detected in other tumor types studied,thus the STAT3 mutations can be used as molecular markers for LGLL diagnosis and can provide a novel therapeutic target for patients with LGLL.