Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells

Takeshi Ishibashi, Akinori Yaguchi, Kazuki Terada, Hitomi Ueno-Yokohata, Osamu Tomita, Kazutoshi Iijima, Kenichiro Kobayashi, Hajime Okita, Junya Fujimura, Kentaro Ohki, Toshiaki Shimizu, Nobutaka Kiyokawa

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)177-188
Number of pages12
JournalExperimental Hematology
Volume44
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1
Externally publishedYes

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Platelet-Derived Growth Factor beta Receptor
Protein-Tyrosine Kinases
Phosphotransferases
Interleukin-3
B-Lymphoid Precursor Cells
Mitogen-Activated Protein Kinase Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cell Death
B-Lymphocyte Subsets
1-Phosphatidylinositol 4-Kinase
Gene Fusion

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Ishibashi, T., Yaguchi, A., Terada, K., Ueno-Yokohata, H., Tomita, O., Iijima, K., ... Kiyokawa, N. (2016). Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells. Experimental Hematology, 44(3), 177-188. https://doi.org/10.1016/j.exphem.2015.11.009

Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells. / Ishibashi, Takeshi; Yaguchi, Akinori; Terada, Kazuki; Ueno-Yokohata, Hitomi; Tomita, Osamu; Iijima, Kazutoshi; Kobayashi, Kenichiro; Okita, Hajime; Fujimura, Junya; Ohki, Kentaro; Shimizu, Toshiaki; Kiyokawa, Nobutaka.

In: Experimental Hematology, Vol. 44, No. 3, 01.03.2016, p. 177-188.

Research output: Contribution to journalArticle

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 2016, 'Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells', Experimental Hematology, vol. 44, no. 3, pp. 177-188. https://doi.org/10.1016/j.exphem.2015.11.009
Ishibashi, Takeshi ; Yaguchi, Akinori ; Terada, Kazuki ; Ueno-Yokohata, Hitomi ; Tomita, Osamu ; Iijima, Kazutoshi ; Kobayashi, Kenichiro ; Okita, Hajime ; Fujimura, Junya ; Ohki, Kentaro ; Shimizu, Toshiaki ; Kiyokawa, Nobutaka. / Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells. In: Experimental Hematology. 2016 ; Vol. 44, No. 3. pp. 177-188.
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AU - Kobayashi, Kenichiro

AU - Okita, Hajime

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