Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.
Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.
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DOI：
10.1038/s41467-018-03987-2
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发表时间：
2018-04-19
影响因子：
16.6
通讯作者：
Mustjoki S
中科院分区：
文献类型：
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作者：
Dufva O;Kankainen M;Kelkka T;Sekiguchi N;Awad SA;Eldfors S;Yadav B;Kuusanmäki H;Malani D;Andersson EI;Pietarinen P;Saikko L;Kovanen PE;Ojala T;Lee DA;Loughran TP Jr;Nakazawa H;Suzumiya J;Suzuki R;Ko YH;Kim WS;Chuang SS;Aittokallio T;Chan WC;Ohshima K;Ishida F;Mustjoki S
侵袭性自然杀伤细胞(NK细胞)白血病是一种高度侵袭性的恶性肿瘤，预后差，缺乏靶向治疗。在这里，我们使用基因组和药物敏感性分析相结合的方法来阐明踝关节的分子发病机制。我们使用全外显子组测序(WES)对14例踝关节患者进行了研究，发现了STAT3(21%)和RAS-MAPK途径基因(21%)以及DDX3X(29%)和表观遗传修饰物(50%)的突变。其他变化包括JAK-STAT拷贝增加和酪氨酸磷酸酶突变，我们通过整合公共基因组数据显示，在结外NK/T细胞淋巴瘤、鼻型淋巴瘤(NKTCL)中也有复发。药物敏感性分析进一步证明了JAK-STAT通路在NK细胞恶性肿瘤发病机制中的作用，发现与其他造血细胞系相比，NK细胞对JAK和BCL2抑制高度敏感。我们的结果提供了对踝关节遗传学的洞察和NK细胞恶性肿瘤靶向治疗的应用框架。侵袭性自然杀伤细胞白血病(Ankl)几乎没有针对性的治疗方法。在这里，据报道，ankl患者存在STAT3、RAS-MAPK途径、DDX3X和表观遗传修饰物突变；药物敏感性分析揭示了JAK-STAT途径的重要性，揭示了潜在的ankl治疗靶点。
Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies. Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.
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影响因子：
14.9
作者：
Gonzalez-Perez A;Lopez-Bigas N
通讯作者：
Lopez-Bigas N
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
10.1
作者：
Couronne, Lucile;Scourzic, Laurianne;Mercher, Thomas
通讯作者：
Mercher, Thomas
影响因子：
11.4
作者：
Bouchekioua, A.;Scourzic, L.;Coppo, P.
通讯作者：
Coppo, P.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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