PLoS ONE (Jan 2017)

Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines.

  • Kazuya Takahashi,
  • Takeshi Inukai,
  • Toshihiko Imamura,
  • Mio Yano,
  • Chihiro Tomoyasu,
  • David M Lucas,
  • Atsushi Nemoto,
  • Hiroki Sato,
  • Meixian Huang,
  • Masako Abe,
  • Keiko Kagami,
  • Tamao Shinohara,
  • Atsushi Watanabe,
  • Shinpei Somazu,
  • Hiroko Oshiro,
  • Koshi Akahane,
  • Kumiko Goi,
  • Jiro Kikuchi,
  • Yusuke Furukawa,
  • Hiroaki Goto,
  • Masayoshi Minegishi,
  • Shotaro Iwamoto,
  • Kanji Sugita

DOI
https://doi.org/10.1371/journal.pone.0188680
Journal volume & issue
Vol. 12, no. 12
p. e0188680

Abstract

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Prognosis of childhood acute lymphoblastic leukemia (ALL) has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ), a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+) ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response. Even in Ph-negative ALL cell lines, IKZF1 deletion and bilallelic loss of CDKN2A were independently associated with higher BTZ sensitivity. BTZ showed only marginal cross-resistance to four representative chemotherapeutic agents (vincristine, dexamethasone, l-asparaginase, and daunorubicin) in B-cell precursor-ALL cell lines. To improve the efficacy and safety of proteasome inhibitor combination chemotherapy, we also analyzed the anti-leukemic activity of carfilzomib (CFZ), a second-generation proteasome inhibitor, as a substitute for BTZ. CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19) ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment. P-glycoprotein inhibitors effectively restored the sensitivity to CFZ, but not BTZ, in P-glycoprotein-positive t(17;19) ALL cell lines. P-glycoprotein overexpressing ALL cell line showed a CFZ-specific resistance, while knockout of P-glycoprotein by genome editing with a CRISPR/Cas9 system sensitized P-glycoprotein-positive t(17;19) ALL cell line to CFZ. These observations suggested that IKZF1 deletion could be a useful biomarker to predict good sensitivity to CFZ and BTZ, and that CFZ combination chemotherapy may be a new therapeutic option with higher anti-leukemic activity for refractory ALL that contain P-glycoprotein-negative leukemia cells.