CAMK2G is identified as a novel therapeutic target for myelofibrosis.
CAMK2G is identified as a novel therapeutic target for myelofibrosis.
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DOI：
10.1182/bloodadvances.2020003303
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发表时间：
2022-03-08
期刊：
影响因子：
7.5
通讯作者：
Kurokawa M
中科院分区：
文献类型：
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作者：
Miyauchi M;Sasaki K;Kagoya Y;Taoka K;Masamoto Y;Yamazaki S;Arai S;Mizuno H;Kurokawa M
CAMK 2G抑制改善MF，减轻脾肿大和白细胞增多，并提高由MPL W515 L诱导的MF小鼠的存活率。CAMK 2G抑制可以是克服耐药性的新的治疗策略。尽管JAK 1/2抑制在缓解骨髓纤维化（MF）的症状方面是有效的，但它不会导致MF克隆的根除，这可能导致在治疗期间出现耐药克隆。在这里，我们建立了源自MF患者样本（MF-iPSC）的诱导多能干细胞（iPSC），其含有JAK 2 V617 F、CALR 1型或CALR 2型突变。我们证明了这些细胞忠实地再现了疾病的药物敏感性。这些细胞被用于化学筛选，钙/钙调蛋白依赖性蛋白激酶2（CAMK 2）被确定为有前途的治疗靶点。MF模型细胞和由MPL W515 L（在MF患者中反复检测到的另一种类型的突变）诱导的小鼠用于阐明CAMK 2抑制的治疗潜力。CAMK 2抑制对JAK 2受体敏感和JAK 2受体耐药细胞有效。进一步研究发现，在MPL W515 L诱导的MF模型细胞中，CAMK 2 γ亚型起重要作用。我们发现，表达MPL W515 L的原代骨髓细胞中的CAMK 2G异质敲除降低了集落形成能力。在MPL W515 L诱导的MF小鼠模型中，用小檗胺（一种CAMK 2G抑制剂）抑制CAMK 2G显著延长了存活期并减少了疾病表型，例如脾肿大和白细胞增多。我们研究了CAMK 2G抑制治疗作用的分子机制，发现CAMK 2G在MF模型细胞中被MPL信号激活，并且是这些细胞中MPL-JAK 2信号通路的效应子。这些结果表明CAMK 2G在MF中起重要作用，并且CAMK 2G抑制可能是克服对JAK 1/2抑制的抗性的新的治疗策略。
CAMK2G inhibition ameliorates MF, lessens splenomegaly and leukocytosis, and enhances survival of MF mice induced by MPL W515L. CAMK2G inhibition can be a novel therapeutic strategy to overcome drug resistance. Although JAK1/2 inhibition is effective in alleviating symptoms of myelofibrosis (MF), it does not result in the eradication of MF clones, which can lead to inhibitor-resistant clones emerging during the treatment. Here, we established induced pluripotent stem cells (iPSCs) derived from MF patient samples (MF-iPSCs) harboring JAK2 V617F, CALR type 1, or CALR type 2 mutations. We demonstrated that these cells faithfully recapitulate the drug sensitivity of the disease. These cells were used for chemical screening, and calcium/calmodulin-dependent protein kinase 2 (CAMK2) was identified as a promising therapeutic target. MF model cells and mice induced by MPL W515L, another type of mutation recurrently detected in MF patients, were used to elucidate the therapeutic potential of CAMK2 inhibition. CAMK2 inhibition was effective against JAK2 inhibitor-sensitive and JAK2 inhibitor-resistant cells. Further research revealed CAMK2 γ subtype was important in MF model cells induced by MPL W515L. We showed that CAMK2G hetero knockout in the primary bone marrow cells expressing MPL W515L decreased colony-forming capacity. CAMK2G inhibition with berbamine, a CAMK2G inhibitor, significantly prolonged survival and reduced disease phenotypes, such as splenomegaly and leukocytosis in a MF mouse model induced by MPL W515L. We investigated the molecular mechanisms underlying the therapeutic effect of CAMK2G inhibition and found that CAMK2G is activated by MPL signaling in MF model cells and is an effector in the MPL-JAK2 signaling pathway in these cells. These results indicate CAMK2G plays an important role in MF, and CAMK2G inhibition may be a novel therapeutic strategy that overcomes resistance to JAK1/2 inhibition.
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影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
DOI：
10.1158/1078-0432.ccr-11-1541
发表时间：
2011-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Fiskus W;Verstovsek S;Manshouri T;Rao R;Balusu R;Venkannagari S;Rao NN;Ha K;Smith JE;Hembruff SL;Abhyankar S;McGuirk J;Bhalla KN
通讯作者：
Bhalla KN
影响因子：
15.8
作者：
Pikman, Yana;Lee, Benjamin H.;Mercher, Thomas;McDowell, Elizabeth;Ebert, Benjamin L.;Gozo, Maricel;Cuker, Adam;Wernig, Gerlinde;Moore, Sandra;Galinsky, Ilene;DeAngelo, Daniel J.;Clark, Jennifer J.;Lee, Stephanie J.;Golub, Todd R.;Wadleigh, Martha;Gilliland, D. Gary;Levine, Ross L.
通讯作者：
Levine, Ross L.
影响因子：
45.3
作者：
Pardanani, Animesh;Gotlib, Jason R.;Tefferi, Ayalew
通讯作者：
Tefferi, Ayalew
影响因子：
8
作者：
通讯作者：
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