t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.
t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.
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DOI：
10.1371/journal.pone.0053767
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
MacLeod RA
中科院分区：
文献类型：
--
作者：
Ehrentraut S;Nagel S;Scherr ME;Schneider B;Quentmeier H;Geffers R;Kaufmann M;Meyer C;Prochorec-Sobieszek M;Ketterling RP;Knudson RA;Feldman AL;Kadin ME;Drexler HG;MacLeod RA
JAK 2的酪氨酸激酶结构域与多个伴侣的融合发生在白血病/淋巴瘤中，据报道它们促进JAK 2寡聚化和自主信号传导。受影响的实体是用JAK 2信号传导抑制剂治疗的有希望的候选者。虽然JAK 2易位发生在骨髓，B细胞和T细胞淋巴肿瘤，我们的研究结果表明，他们的发病率在最后一组低。在这里，我们描述了由t（8;9）（p22;p24）在皮肤T细胞淋巴瘤（CTCL）的惰性（MAC-1）和侵袭性（MAC-2A/2B）阶段建立的三个细胞系中形成的PCM 1-JAK 2的基因组，转录和信号特征。为了研究信号传导，对PCM 1-JAK 2进行慢病毒敲低，其抑制t（8;9）细胞中7个最高上调的基因，特别是SOCS 2/3。SOCS 3，而不是SOCS 2，也上调慢性嗜酸性粒细胞白血病轴承PCM 1-JAK 2，突出了其作为JAK 2易位瘤的中央信号转导靶点的作用。相反，GATA 3的表达，一个关键的T细胞发育基因沉默的侵袭性淋巴瘤细胞，部分恢复PCM 1-JAK 2敲低。用MAC-1/2A/2B细胞对其显著敏感的选择性JAK 2抑制剂（TG 101348）处理证实了敲低结果，并突出JAK 2为活性部分。PCM 1-JAK 2信号传导需要pSTAT 5，支持淋巴恶性肿瘤中JAK 2改变激活STAT 5的一般模式。MAC-1/2A/2B -描述的第一个JAK 2易位白血病/淋巴瘤细胞系-显示出明显的JAK/STAT信号传导伴随着T细胞发育和自身免疫性疾病基因表达特征，证实了它们作为CTCL疾病模型的适合性。我们的数据支持进一步研究SOCS 2/3作为JAK 2重排癌症的信号效应子、预后指标和潜在治疗靶点。
Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2–translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.
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影响因子：
32.4
作者：
Chen E;Staudt LM;Green AR
通讯作者：
Green AR
影响因子：
32.4
作者：
Babon JJ;Kershaw NJ;Murphy JM;Varghese LN;Laktyushin A;Young SN;Lucet IS;Norton RS;Nicola NA
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Nicola NA
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20.3
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Odum, N
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Ho, JMY;Beattie, BK;Barber, DL
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Barber, DL