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, 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 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.

Center for Stem Cell Medicine Chinese Academy of Medical Sciences Beijing China

Department of Hematology and Oncology Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou China

Department of Oncology St Jude Children's Research Hospital Memphis TN

Department of Pharmaceutical Sciences St Jude Children's Research Hospital Memphis TN

Division of Pediatric Blood Diseases Center Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin China

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czech Republic; and

Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences Beijing China

State Key Laboratory of Experimental Hematology Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin China

University of Chinese Academy of Sciences Beijing China

Blood. 2018 May 17;131(20):2181-2182. doi: 10.1182/blood-2018-03-833665. PubMed

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New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia