%0 Journal Article
%T Potent antiproliferative effect of fatty©\acid derivative AIC©\47 on leukemic mice harboring BCR©\ABL mutation
%A Haruka Shinohara
%A Kazuki Heishima
%A Nobuhiko Sugito
%A Tomoki Naoe
%A Yosuke Minami
%A Yuki Kuranaga
%A Yukihiro Akao
%J Archive of "Cancer Science".
%D 2019
%R 10.1111/cas.13913
%X Therapy based on targeted inhibition of BCR©\ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)©\positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR©\ABL. We previously reported that a medium©\chain fatty©\acid derivative AIC©\47 induced transcriptional suppression of BCR©\ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph©\positive leukemia cells. Herein, we showed that AIC©\47 had anti©\leukemic effects in either wild type (WT)©\ or mutated©\BCR©\ABL©\harboring cells. AIC©\47 suppressed transcription of BCR©\ABL gene regardless of the mutation through downregulation of transcriptional activator, c©\Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti©\cancer drugs; however, we found that a point mutation of BCR©\ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I©\mutated cells, AIC©\47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC©\47 disrupted the Warburg effect. In a leukemic mouse model, AIC©\47 greatly suppressed the increase in BCR©\ABL mRNA level and improved hepatosplenomegaly regardless of the BCR©\ABL mutation. Notably, the improvement of splenomegaly by AIC©\47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC©\47 might be a promising agent for overcoming the resistance of Ph©\positive leukemia to therapy
%K BCR©\ABL
%K leukemic mouse model
%K resistance
%K translational research
%K Warburg effect
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361563/