論文 - 詳細
| RRC ID | 30713 |
|---|---|
| 著者 | Nagao T, Kurosu T, Umezawa Y, Nogami A, Oshikawa G, Tohda S, Yamamoto M, Miura O. |
| タイトル | Proliferation and survival signaling from both Jak2-V617F and Lyn involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 cell line newly established from acute myeloid leukemia transformed from polycythemia vera. |
| ジャーナル | PLoS One |
| Abstract |
The gain of function mutation JAK2-V617F is very frequently found in myeloproliferative neoplasms (MPNs) and is strongly implicated in pathogenesis of these and other hematological malignancies. Here we report establishment of a new leukemia cell line, PVTL-1, homozygous for JAK2-V617F from a 73-year-old female patient with acute myeloid leukemia (AML) transformed from MPN. PVTL-1 is positive for CD7, CD13, CD33, CD34, CD117, HLA-DR, and MPO, and has complex karyotypic abnormalities, 44,XX,-5q,-7,-8,add(11)(p11.2),add(11)(q23),-16,+21,-22,+mar1. Sequence analysis of JAK2 revealed only the mutated allele coding for Jak2-V617F. Proliferation of PVTL-1 was inhibited and apoptosis was induced by the pan-Jak inhibitor Jak inhibitor-1 (JakI-1) or dasatinib, which inhibits the Src family kinases as well as BCR/ABL. Consistently, the Src family kinase Lyn was constitutively activated with phosphorylation of Y396 in the activation loop, which was inhibited by dasatinib but not by JakI-1. Further analyses with JakI-1 and dasatinib indicated that Jak2-V617F phosphorylated STAT5 and SHP2 while Lyn phosphorylated SHP1, SHP2, Gab-2, c-Cbl, and CrkL to induce the SHP2/Gab2 and c-Cbl/CrkL complex formation. In addition, JakI-1 and dasatinib inactivated the mTOR/p70S6K/4EBP1 pathway and reduced the inhibitory phosphorylation of GSK3 in PVTL-1 cells, which correlated with their effects on proliferation and survival of these cells. Furthermore, inhibition of GSK3 by its inhibitor SB216763 mitigated apoptosis induced by dasatinib but not by JakI-1. Together, these data suggest that apoptosis may be suppressed in PVTL-1 cells through inactivation of GSK3 by Lyn as well as Jak2-V617F and additionally through activation of STAT5 by Jak2-V617F. It is also speculated that activation of the mTOR/p70S6K/4EBP1 pathway may mediate proliferation signaling from Jak2-V617F and Lyn. PVTL-1 cells may provide a valuable model system to elucidate the molecular mechanisms involved in evolution of Jak2-V617F-expressing MPN to AML and to develop novel therapies against this intractable condition. |
| 巻・号 | 9(1) |
| ページ | e84746 |
| 公開日 | 2014-1-1 |
| DOI | 10.1371/journal.pone.0084746 |
| PII | PONE-D-13-34652 |
| PMID | 24404189 |
| PMC | PMC3880321 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism* Apoptosis / drug effects Bone Marrow / metabolism Bone Marrow / pathology Cell Cycle Proteins Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Cell Survival / genetics Cell Transformation, Neoplastic / genetics Cell Transformation, Neoplastic / metabolism DNA Mutational Analysis Dasatinib Female Glycogen Synthase Kinase 3 / metabolism* Humans Janus Kinase 2 / genetics Janus Kinase 2 / metabolism* Karyotype Leukemia, Myeloid, Acute / diagnosis Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism* Middle Aged Mutation Phosphoproteins / metabolism* Phosphorylation / drug effects Polycythemia Vera / diagnosis Polycythemia Vera / genetics Polycythemia Vera / metabolism* Protein Kinase Inhibitors / pharmacology Pyrimidines / pharmacology Ribosomal Protein S6 Kinases, 70-kDa / metabolism* Signal Transduction / drug effects Thiazoles / pharmacology src-Family Kinases / genetics src-Family Kinases / metabolism* |
| IF | 2.74 |
| 引用数 | 17 |
| WOS 分野 | HEMATOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pRx nZ ires Neo (RDB01699). |