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

0491312 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
Zhang, Y. - Gao, Y. - Zhang, H. - Zhang, J. - He, F. - Hnízda, Aleš - Qian, M. - Liu, X. M. - Gocho, Y. - Pui, C. H. - Cheng, T. - Wang, Q. - Yang, J. J. - Zhu, X. - Liu, X.
PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia.
Blood. Roč. 131, č. 20 (2018), s. 2256-2261. ISSN 0006-4971. E-ISSN 1528-0020
Grant CEP: GA ČR GA15-06582S
Institucionální podpora: RVO:61388963
Klíčová slova: children’s oncology group * high-risk * imatinib
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 16.601, rok: 2018
http://www.bloodjournal.org/content/131/20/2256

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises similar to 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.
Trvalý link: http://hdl.handle.net/11104/0285303