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

Authors
  • Zhang, Yingchi1
  • Gao, Yufeng2, 3
  • Zhang, Hui4, 5
  • Zhang, Jingliao1, 1, 6
  • He, Fuhong2, 3
  • Hnízda, Aleš7
  • Qian, Maoxiang4
  • Liu, Xiaoming1, 1, 6
  • Gocho, Yoshihiro4
  • Pui, Ching-Hon8
  • Cheng, Tao1, 1, 6
  • Wang, Qianfei2, 3
  • Yang, Jun J.4, 8
  • Zhu, Xiaofan1, 1, 6
  • Liu, Xin2, 3
  • 1 & Peking Union Medical College, Tianjin, China;
  • 2 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;
  • 3 University of Chinese Academy of Sciences, Beijing, China;
  • 4 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
  • 5 Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China;
  • 6 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China;
  • 7 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic; and
  • 8 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 17, 2018
Volume
131
Issue
20
Pages
2256–2261
Identifiers
DOI: 10.1182/blood-2017-11-817510
PMID: 29434033
PMCID: PMC5958655
Source
PubMed Central
License
Unknown

Abstract

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB -rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are 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, PDGFRB C843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB -mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.

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