Perturbation of p38α mapk as a novel strategy to effectively sensitize chronic myeloid leukemia cells to therapeutic bcr-abl inhibitors

Yi Hue Kuo, Shih Hsiang Wei, Jie Hau Jiang, Yueh Shih Chang, Mei Yin Liu, Shu Ling Fu, Chi Ying F. Huang, Wey Jinq Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib-and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.

Original languageEnglish
Article number12573
JournalInternational Journal Of Molecular Sciences
Issue number22
StatePublished - 1 Nov 2021


  • Chronic myeloid leukemia
  • Combined therapy
  • Dasatinib
  • Imatinib
  • P38 MAPK


Dive into the research topics of 'Perturbation of p38α mapk as a novel strategy to effectively sensitize chronic myeloid leukemia cells to therapeutic bcr-abl inhibitors'. Together they form a unique fingerprint.

Cite this