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 - Funding Information:
R. Balusu acknowledges the pilot award from American Cancer Society (ACS-IRG-16-194-07), Sosland Family Foundation Research Award, Hale Family Foundation, and Frontiers Clinical and Translational Pilot Award UL1T. R.A. Jensen was a recipient of P30-CA168524 from NCI. We are very grateful to Riley Baker (University of Kansas Medical Student) for thorough proofreading of the article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
R. Balusu acknowledges the pilot award from American Cancer Society (ACS-IRG-16-194-07), Sosland Family Foundation Research Award, Hale Family Foundation, and Frontiers Clinical and Translational Pilot Award UL1T. R.A. Jensen was a recipient of P30-CA168524 from NCI. We are very grateful to Riley Baker (University of Kansas Medical Student) for thorough proofreading of the article.
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
VL - 19
SP - 913
EP - 920
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 5
ER -