骨髓增殖性肿瘤（MPN）是造血干细胞恶性增殖性疾病，近年发现与JAK2基因突变激活细胞JAK/STAT信号通路会导致细胞恶性增殖。但是迄今还不清楚，为何增殖的细胞会演化为红系（真性红细胞增多症），巨核细胞-血小板系统（血小板增多症）,成纤维细胞系（骨髓纤维化）以及髓细胞系（慢粒白血病）等不同的恶性克隆。我们用单细胞全基因组测序首次发现MPN发病经历体细胞克隆演化过程，又从一批病例发现，该信号通路的抑制基因LNK的不同基因型有可能诱导恶性细胞向不同造血细胞系列分化。拟用不同基因型的LNK载体转染和培养患者骨髓细胞和细胞系，用抗体和siRNA干扰LNK功能，做体外实验；用不同的LNK载体转染的LNK敲除小鼠骨髓细胞进行异基因骨髓移植，做体内试验；分别观察造血细胞的分化方向。用ChIP on Chip技术寻找和确定LNK抑制JAK/STAT信号后影响细胞分化的关键基因，探索将来靶向治疗的可能性

Myeloproliferative neoplasms (MPN) is a hematopoietic stem cell malignant hyperplastic disease. Studies have recently found that MPN is related to JAK2 gene mutations, leading to hyperactivation of JAK/STAT signal pathway and malignant proliferation. But we don't know why proliferation cells finally evolve into different malignant clones of erythrocyte system (polycythemia vera, PV), megakaryocyte-platelet system (essential thrombocythemia, ET), fibroblasts system (idiopathic myelofibrosis，IMF) or myelocyte system (chronic myeloid leukemia, CML). We previously used the single cell whole genome sequencing and found that MPN experienced evolutionary processes of somatic cell clones. JAK/STAT signaling pathways have a suppressor of LNK. From a cohort of MPN patients, we also found that LNK gene of different genotypes may induce malignant cells to different series of hematopoietic cell differentiation. In this ongoing study, we will perform in vitro experiment, which uses vectors containing different LNK genotypes to transfect bone marrow cells of MPN patients and related cell lines, and siRNA to knockdown LNK expression to observe cell differentiation direction. We will do in vivo test, which uses vectors of different LNK genotypes to transfect LNK-/- mouse bone marrow cells, then uses these transfected cells for bone marrow transplantation, to observe bone marrow hematopoietic cell differentiation direction. We will also use the ChIP on Chip technology, to find out the key genes which affect cell differentiation after suppression of JAK/STAT signal pathway by different genotypes of LNK. Our study will be helpful for the exploration of target therapy.