The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease.
The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease.
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DOI：
10.1186/1756-8722-7-45
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发表时间：
2014-06-21
影响因子：
28.5
通讯作者：
Welsh M
中科院分区：
文献类型：
--
作者：
Gustafsson K;Jamalpour M;Trinh C;Kharas MG;Welsh M
Src同源2结构域蛋白B（ShB）是在几种酪氨酸激酶受体下游起作用的衔接蛋白，因此ShB调节各种细胞应答。Shb的缺乏最近被证明通过激活粘着斑激酶（FAK）减少造血干细胞增殖，因此我们试图研究Shb在白血病进展中的作用。用逆转录病毒BCR-ABL构建体转化野生型和Shb敲除骨髓细胞，随后移植至野生型或Shb敲除受体。通过流式细胞术、qPCR、蛋白质印迹和甲基纤维素集落形成测定来确定疾病潜伏期、骨髓和外周血细胞特征、细胞因子表达、信号传导特征和集落形成。观察到Shb敲除BCR-ABL转化的骨髓细胞与相应的野生型对照相比，由于转化的骨髓细胞增殖增加，导致在更早的时间点发生死亡的疾病。此外，在Shb敲除c-Kit +白血病骨髓细胞中观察到白细胞介素-6和粒细胞集落刺激因子mRNA水平显著升高，为并发外周血嗜中性粒细胞提供了合理的解释。Shb基因敲除的白血病骨髓细胞也表现出在缺乏细胞因子的甲基纤维素中形成集落的能力增加，这依赖于伴随观察到的FAK活性增加。将BCR-ABL转化的Shb基因敲除骨髓细胞移植给Shb基因敲除受体，发现疾病潜伏期缩短，但无嗜中性粒细胞，因此暗示了小生境来源的线索对血液粒细胞增加的重要性。Shb缺乏通过在BCR-ABL诱导的白血病中发挥双重作用加速疾病进展：由于FAK活性升高导致的细胞扩增增加和外周血嗜中性粒细胞增多，后者依赖于白血病小生境的遗传背景。
The Src homology-2 domain protein B (Shb) is an adapter protein operating downstream of several tyrosine kinase receptors and consequently Shb regulates various cellular responses. Absence of Shb was recently shown to reduce hematopoietic stem cell proliferation through activation of focal adhesion kinase (FAK) and thus we sought to investigate Shb’s role in the progression of leukemia. Wild type and Shb knockout bone marrow cells were transformed with a retroviral BCR-ABL construct and subsequently transplanted to wild type or Shb knockout recipients. Disease latency, bone marrow and peripheral blood cell characteristics, cytokine expression, signaling characteristics and colony formation were determined by flow cytometry, qPCR, western blotting and methylcellulose colony forming assays. It was observed that Shb knockout BCR-ABL-transformed bone marrow cells produced a disease with death occurring at earlier time points compared with corresponding wild type controls due to elevated proliferation of transformed bone marrow cells. Moreover, significantly elevated interleukin-6 and granulocyte colony-stimulation factor mRNA levels were observed in Shb knockout c-Kit + leukemic bone marrow cells providing a plausible explanation for the concurrent peripheral blood neutrophilia. Shb knockout leukemic bone marrow cells also showed increased ability to form colonies in methylcellulose devoid of cytokines that was dependent on the concomitantly observed increased activity of FAK. Transplanting BCR-ABL-transformed Shb knockout bone marrow cells to Shb knockout recipients revealed decreased disease latency without neutrophilia, thus implicating the importance of niche-derived cues for the increase of blood granulocytes. Absence of Shb accelerates disease progression by exerting dual roles in BCR-ABL-induced leukemia: increased cell expansion due to elevated FAK activity and neutrophilia in peripheral blood, the latter dependent on the genetic background of the leukemic niche.
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影响因子：
3.7
作者：
Gustafsson, Karin;Heffner, Garrett;Welsh, Michael
通讯作者：
Welsh, Michael
影响因子：
3.7
作者：
Hagerkvist, Robert;Mokhtari, Dariush;Welsh, Michael
通讯作者：
Welsh, Michael
DOI：
10.1056/nejmoa1214514
发表时间：
2013-05-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maxson JE;Gotlib J;Pollyea DA;Fleischman AG;Agarwal A;Eide CA;Bottomly D;Wilmot B;McWeeney SK;Tognon CE;Pond JB;Collins RH;Goueli B;Oh ST;Deininger MW;Chang BH;Loriaux MM;Druker BJ;Tyner JW
通讯作者：
Tyner JW
DOI：
10.1084/jem.189.9.1399
发表时间：
1999-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li S;Ilaria RL Jr;Million RP;Daley GQ;Van Etten RA
通讯作者：
Van Etten RA
影响因子：
2.5
作者：
Kriz, Vitezslav;Mares, Jaroslav;Welsh, Michael
通讯作者：
Welsh, Michael