@article{1932c222ee044fedbb3a982a6f60e757,
title = "In-vitro modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene RANBP2-ABL1 - implications for targeted therapy",
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 = "ABL-class fusions, Acute lymphoblastic leukemia, Ph-like ALL, TKI resistance, asciminib",
author = "Heatley, {Susan L.} and Kartini Asari and Schutz, {Caitlin E.} and Leclercq, {Tamara M.} and McClure, {Barbara J.} and Eadie, {Laura N.} and Hughes, {Timothy P.} and Yeung, {David T.} and White, {Deborah L.}",
note = "Funding Information: This work is funded by National Health and Medical Research Council (NHMRC), Australia [APP1057746, APP1044884]; Leukemia Foundation, Australia; Cancer Council of South Australia, Adelaide, SA, Australia; Beat Cancer, Adelaide, SA, Australia. SLH is The Kids Cancer Project Postdoctoral Research Fellow. KA is the recipient of the Melissa White Memorial PhD Scholarship, the Statewide Super Research Scholarship and the Beat Cancer Top-up Scholarship. LNE is the Peter Nelson Leukemia Research Fellow. TPH is the Beat Cancer Professor and Chair of the Cancer Council in Cancer Research, SA. DTY is an NHMRC Early Career Fellow. DLW is the NHMRC RD Wright Fellow and the Beat Cancer Principal Research Fellow. The authors would like to thank Professor Charles Mullighan and Dr Kathryn Roberts (St Jude Children?s Research Hospital) for the provision of the patient derived RANBP2-ABL1 fusion gene construct; Professor Andrew Zannetinno and Dr Stephen Fitter (University of Adelaide) for the provision of the Ba/F3 cell line and technical advice on cloning. The authors also thank Dr Chung Hoow Kok (SAHMRI) for statistical assistance.",
year = "2021",
doi = "10.1080/10428194.2020.1861275",
language = "English",
volume = "62",
pages = "1157--1166",
journal = "Leukemia and Lymphoma",
issn = "1042-8194",
publisher = "Informa Healthcare",
number = "5",
}