TY - JOUR
T1 - Preclinical evaluation of gilteritinib on NPM1-ALK-driven anaplastic large cell lymphoma cells
AU - Kuravi, Sudhakiranmayi
AU - Cheng, Janice
AU - Fangman, Gabrielle
AU - Polireddy, Kishore
AU - McCormick, Sophia
AU - Lin, Tara L.
AU - Singh, Anurag K.
AU - Abhyankar, Sunil
AU - Ganguly, Siddhartha
AU - Welch, Danny R.
AU - Jensen, Roy A.
AU - McGuirk, Joseph P.
AU - Balusu, Ramesh
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinibmediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. Weutilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0-G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies.
AB - Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinibmediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. Weutilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0-G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies.
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U2 - 10.1158/1541-7786.MCR-20-0738
DO - 10.1158/1541-7786.MCR-20-0738
M3 - Article
C2 - 33514657
AN - SCOPUS:85105350485
SN - 1541-7786
VL - 19
SP - 913
EP - 920
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -