| RRC ID |
61921
|
| 著者 |
Ishibashi T, Yaguchi A, Terada K, Ueno-Yokohata H, Tomita O, Iijima K, Kobayashi K, Okita H, Fujimura J, Ohki K, Shimizu T, Kiyokawa N.
|
| タイトル |
Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells.
|
| ジャーナル |
Exp Hematol
|
| Abstract |
ATF7IP-PDGFRB is a novel PDGFRB-related fusion gene identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with a signature similar to that of Ph1 ALL, so-called Ph-like ALL. When we introduced ATF7IP-PDGFRB, murine Ba/F3 cells acquired the ability to proliferate in an interleukin (IL)-3-independent manner. On the contrary, the expression of wild-type PDGFRB is not sufficient to acquire the ability for IL-3-independent proliferation in Ba/F3 cells. The introduction of ATF7IP-PDGFRB also induces a typical gene expression profile for Ph1-ALL in Ba/F3 cells. A series of biochemical and cell biological experiments revealed the constitutive activation of ATF7IP-PDGFRB as well as downstream signaling molecules, including AKT and MAPK. Although the phosphoinositide 3-kinase inhibitor led to cell death in both cells into which ATF7IP-PDGFRB had been introduced and IL-3-maintained Mock cells, MEK inhibitor selectively led to cell death into which ATF7IP-PDGFRB had been introduced. The introduction of tyrosine to phenylalanine mutations at binding sites of adaptor molecules important in the MAPK pathway located in the PDGFRB portion abolished ATF7IP-PDGFRB-mediated cell transformation, suggesting that MAPK-mediated signals are critical in ATF7IP-PDGFRB-mediated cell transformation. On treatment with tyrosine kinase inhibitors, ATF7IP-PDGFRB-expressing, but not Mock, Ba/F3 cells underwent rapid apoptosis accompanied by reduced phosphorylation of MAPK. Importantly, the sensitivity of ATF7IP-PDGFRB-expressing Ba/F3 cells to imatinib is significantly higher than that of BCR-ABL1-transformed Ba/F3 cells, as assessed by the IC50. Taken together, ATF7IP-PDGFRB has transforming potential via the constitutive activation of MAPK and participates in the pathogenesis of Ph-like ALL. Our observations suggest the therapeutic importance of tyrosine kinase inhibitors and possibly MEK inhibitor for a subset of BCP-ALL harboring PDGFRB-related fusion kinases.
|
| 巻・号 |
44(3)
|
| ページ |
177-88.e5
|
| 公開日 |
2016-3-1
|
| DOI |
10.1016/j.exphem.2015.11.009
|
| PII |
S0301-472X(15)00795-X
|
| PMID |
26703895
|
| MeSH |
Animals
Cell Line, Tumor
Gene Expression Regulation, Leukemic / drug effects*
Humans
Mice
Oncogene Proteins, Fusion* / antagonists & inhibitors
Oncogene Proteins, Fusion* / biosynthesis
Oncogene Proteins, Fusion* / genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / enzymology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / pathology
Protein Kinase Inhibitors / pharmacology*
Receptor, Platelet-Derived Growth Factor beta* / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta* / biosynthesis
Receptor, Platelet-Derived Growth Factor beta* / genetics
Repressor Proteins* / antagonists & inhibitors
Repressor Proteins* / biosynthesis
Repressor Proteins* / genetics
|
| IF |
2.82
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805)
WEHI-3(RCB0035) |
