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PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia

Yingchi Zhang, Yufeng Gao, Hui Zhang, Jingliao Zhang, Fuhong He, Aleš Hnízda, Maoxiang Qian, Xiaoming Liu, Yoshihiro Gocho, Ching-Hon Pui, Tao Cheng, Qianfei Wang, Jun J. Yang, Xiaofan Zhu and Xin Liu

Key points

  • AGGF1-PDGFRB is a novel oncogenic fusion gene in Ph-like ALL

  • Genomic profiling and functional studies identified a novel PDGFRB mutation directly related to tyrosine kinase inhibitor resistance

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) comprises of approximately 10-15% of childhood ALL cases, many of whom respond exquisitely to tyrosine kinase inhibitors (TKIs), e.g., imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs with mechanisms poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation PDGFRBC843G, which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multi-target kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients with resistant to ABL TKIs. In summary, we described complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drive leukemia relapse after ABL TKI treatment.

  • Submitted November 21, 2017.
  • Accepted February 2, 2018.