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Type: Journal article
Title: In-vitro modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene RANBP2-ABL1 - implications for targeted therapy
Author: Heatley, S.L.
Asari, K.
Schutz, C.E.
Leclercq, T.M.
McClure, B.J.
Eadie, L.N.
Hughes, T.P.
Yeung, D.T.
White, D.L.
Citation: Leukemia and Lymphoma, 2021; 62(5):1157-1166
Publisher: Taylor & Francis
Issue Date: 2021
ISSN: 1042-8194
Statement of
Susan L. Heatley, Kartini Asari, Caitlin E. Schutz, Tamara M. Leclercq, Barbara J. McClure, Laura N. Eadie , Timothy P. Hughes, David T. Yeung and Deborah L. White
Abstract: Acute lymphoblastic leukemia remains a leading cause of cancer-related death in children. Furthermore, subtypes such as Ph-like ALL remain at high-risk of relapse, and treatment resistance remains a significant clinical issue. The patient-derived Ph-like ALL RANBP2-ABL1 fusion gene was transduced into Ba/F3 cells and allowed to become resistant to the tyrosine kinase inhibitors (TKIs) imatinib or dasatinib, followed by secondary resistance to ponatinib. RANBP2-ABL1 Ba/F3 cells developed the clinically relevant ABL1 p.T315I mutation and upon secondary resistance to ponatinib, developed compound mutations, including a novel ABL1 p.L302H mutation. Significantly, compound mutations were targetable with a combination of asciminib and ponatinib. In-vitro modeling of Ph-like ALL RANBP2-ABL1 has identified kinase domain mutations in response to TKI treatment, that may have important clinical ramifications. Early detection of mutations is paramount to guide treatment strategies and improve survival in this high-risk group of patients.
Keywords: Acute lymphoblastic leukemia; Ph-like ALL; TKI resistance; asciminib; ABL-class fusions
Description: .
Rights: © 2020 Informa UK Limited, trading as Taylor & Francis Group
DOI: 10.1080/10428194.2020.1861275
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