TY - JOUR
T1 - Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells
AU - Ishibashi, Takeshi
AU - Yaguchi, Akinori
AU - Terada, Kazuki
AU - Ueno-Yokohata, Hitomi
AU - Tomita, Osamu
AU - Iijima, Kazutoshi
AU - Kobayashi, Kenichiro
AU - Okita, Hajime
AU - Fujimura, Junya
AU - Ohki, Kentaro
AU - Shimizu, Toshiaki
AU - Kiyokawa, Nobutaka
N1 - Funding Information:
This work was supported in part by a Health and Labour Sciences Research Grant (3rd-Term Comprehensive 10-Year Strategy for Cancer Control H22-011); a grant from the National Center for Child Health and Development (26-20), Ministry of Health, Labour and Welfare of Japan ; grants from the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO, 10-41, 10-42, 10-43, 10-44, 10-45); a Grant-in-Aid for Young Scientists (B) (25860899), Tailor-made Medical Treatment Program (BioBank Japan: BBJ), Ministry of Education, Culture, Sports, Science and Technology of Japan ; and a grant for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development , AMED.
Publisher Copyright:
© 2016 ISEH - International Society for Experimental Hematology.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.exphem.2015.11.009
DO - 10.1016/j.exphem.2015.11.009
M3 - Article
C2 - 26703895
AN - SCOPUS:84960129149
VL - 44
SP - 177-188.e5
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 3
ER -
