Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain
Abstract: ABL2 rearranged (ABL2r) acute lymphoblastic leukemia (ALL) is a subtype of high-risk Philadelphia chromosome–like ALL. Patients with ABL2r ALL are treated with high-dose multiagent chemotherapy, and the addition of tyrosine kinase inhibitors to their treatment regimen is currently being ex...
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Elsevier
2025-08-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328025000445 |
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| author | Elias Lagonik Elyse C. Page John B. Bruning Laura N. Eadie Susan L. Heatley Matthew Greenwood Chun Y. Fong Andrew S. Moore David T. Yeung Timothy P. Hughes Deborah L. White |
| author_facet | Elias Lagonik Elyse C. Page John B. Bruning Laura N. Eadie Susan L. Heatley Matthew Greenwood Chun Y. Fong Andrew S. Moore David T. Yeung Timothy P. Hughes Deborah L. White |
| author_sort | Elias Lagonik |
| collection | DOAJ |
| description | Abstract: ABL2 rearranged (ABL2r) acute lymphoblastic leukemia (ALL) is a subtype of high-risk Philadelphia chromosome–like ALL. Patients with ABL2r ALL are treated with high-dose multiagent chemotherapy, and the addition of tyrosine kinase inhibitors to their treatment regimen is currently being explored. We have previously demonstrated the in vitro sensitivity of cells harboring the ZC3HAV1::ABL2 fusion to asciminib, the first inhibitor that specifically targets the Abl myristate pocket (STAMP). In this study, we extended these in vitro findings to demonstrate similar sensitivity to the second-generation STAMP inhibitor, TERN-701, using ZC3HAV1::ABL2 ALL cells. In addition, using truncated ZC3HAV1::ABL2 isoforms, we identified that exon 3 of Abl2 (encoded by ABL2) is essential for the efficacy of both STAMP inhibitors. In an in silico model, we further demonstrated that different myristate pocket residues impact the effective binding of asciminib to Abl2 compared to Abl. Importantly, this suggests that, in the clinical setting, different asciminib binding site mutations may be anticipated with STAMP treatment for ABL2r ALL. Finally, we demonstrated the efficacy of both STAMP inhibitors against cells from patients with ZC3HAV1::ABL2 and asciminib as a novel treatment for ZC3HAV1::ABL2 disease in a preclinical in vivo study. |
| format | Article |
| id | doaj-art-9f64df33b3e14a26b2eaaaad44ce5c64 |
| institution | DOAJ |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-9f64df33b3e14a26b2eaaaad44ce5c642025-08-20T03:15:39ZengElsevierBlood Neoplasia2950-32802025-08-012310010910.1016/j.bneo.2025.100109Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domainElias Lagonik0Elyse C. Page1John B. Bruning2Laura N. Eadie3Susan L. Heatley4Matthew Greenwood5Chun Y. Fong6Andrew S. Moore7David T. Yeung8Timothy P. Hughes9Deborah L. White10Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, AustraliaSchool of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA, Australia; Institute for Photonics and Advanced Sensing, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, AustraliaDepartment of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Australasian Leukaemia & Lymphoma Group, Richmond, VIC, AustraliaAustralasian Leukaemia & Lymphoma Group, Richmond, VIC, Australia; Department of Clinical Haematology, Olivia Newton-John Cancer Centre, Austin Health and The University of Melbourne, Melbourne, VIC, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC, AustraliaOncology Service, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia; Childhood Leukaemia Research Laboratory, The University of Queensland, Brisbane, QLD, Australia; Australian and New Zealand Children’s Haematology-Oncology Group, Clayton, VIC, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia; Australasian Leukaemia & Lymphoma Group, Richmond, VIC, Australia; Haematology Department, Royal Adelaide Hospital, Adelaide, SA, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia; Australasian Leukaemia & Lymphoma Group, Richmond, VIC, Australia; Haematology Department, Royal Adelaide Hospital, Adelaide, SA, AustraliaBlood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA, Australia; School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia; Australasian Leukaemia & Lymphoma Group, Richmond, VIC, Australia; Australian and New Zealand Children’s Haematology-Oncology Group, Clayton, VIC, Australia; Correspondence: Deborah L. White, Precision Cancer Medicine, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia;Abstract: ABL2 rearranged (ABL2r) acute lymphoblastic leukemia (ALL) is a subtype of high-risk Philadelphia chromosome–like ALL. Patients with ABL2r ALL are treated with high-dose multiagent chemotherapy, and the addition of tyrosine kinase inhibitors to their treatment regimen is currently being explored. We have previously demonstrated the in vitro sensitivity of cells harboring the ZC3HAV1::ABL2 fusion to asciminib, the first inhibitor that specifically targets the Abl myristate pocket (STAMP). In this study, we extended these in vitro findings to demonstrate similar sensitivity to the second-generation STAMP inhibitor, TERN-701, using ZC3HAV1::ABL2 ALL cells. In addition, using truncated ZC3HAV1::ABL2 isoforms, we identified that exon 3 of Abl2 (encoded by ABL2) is essential for the efficacy of both STAMP inhibitors. In an in silico model, we further demonstrated that different myristate pocket residues impact the effective binding of asciminib to Abl2 compared to Abl. Importantly, this suggests that, in the clinical setting, different asciminib binding site mutations may be anticipated with STAMP treatment for ABL2r ALL. Finally, we demonstrated the efficacy of both STAMP inhibitors against cells from patients with ZC3HAV1::ABL2 and asciminib as a novel treatment for ZC3HAV1::ABL2 disease in a preclinical in vivo study.http://www.sciencedirect.com/science/article/pii/S2950328025000445 |
| spellingShingle | Elias Lagonik Elyse C. Page John B. Bruning Laura N. Eadie Susan L. Heatley Matthew Greenwood Chun Y. Fong Andrew S. Moore David T. Yeung Timothy P. Hughes Deborah L. White Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain Blood Neoplasia |
| title | Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain |
| title_full | Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain |
| title_fullStr | Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain |
| title_full_unstemmed | Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain |
| title_short | Activity of STAMP inhibitors in ABL2 rearranged acute lymphoblastic leukemia is dependent on the Abl2 SH3 domain |
| title_sort | activity of stamp inhibitors in abl2 rearranged acute lymphoblastic leukemia is dependent on the abl2 sh3 domain |
| url | http://www.sciencedirect.com/science/article/pii/S2950328025000445 |
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