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

• Published in: Blood Vol. 131; no. 20; pp. 2256 - 2261
• Main Authors: Zhang, Yingchi, Gao, Yufeng, Zhang, Hui, Zhang, Jingliao, He, Fuhong, Hnízda, Aleš, Qian, Maoxiang, Liu, Xiaoming, Gocho, Yoshihiro, Pui, Ching-Hon, Cheng, Tao, Wang, Qianfei, Yang, Jun J., Zhu, Xiaofan, Liu, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2018; American Society of Hematology
• Subjects: Angiogenic Proteins - genetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Brief Report; Cell Line, Tumor; Child, Preschool; CME; Drug Resistance, Neoplasm - genetics; Humans; Lymphoid Neoplasia; Male; Mutation; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor, Platelet-Derived Growth Factor beta - genetics; Recurrence; Treatment Outcome; Whole Genome Sequencing
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2017-11-817510

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. •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 TKI resistance.