Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia
department or school: Medicine, Faculty of
department or school: Non UBC
department or school: Medical Genetics, Department of
department or school: Medicine, Department of
data provider: DSpace
identifier citation: International Journal of Molecular Sciences 25 (6): 3307 (2024)
contributor: BC Cancer Research Centre. Terry Fox Laboratory
creator: Wu, Andrew
creator: Liu, Xiaohu
creator: Fruhstorfer, Clark
creator: Jiang, Xiaoyan
issued: 2024-04-23T20:17:02Z
issued: 2024-03-14
description: Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/87940
note: Citation: Wu, A.; Liu, X.; Fruhstorfer,C.; Jiang, X. Clinical Insights intoStructure, Regulation, and Targetingof ABL Kinases in Human Leukemia.Int. J. Mol. Sci. 2024, 25, 3307.https://doi.org/10.3390/ijms25063307Academic Editor: Myunggon KoReceived: 21 February 2024Revised: 12 March 2024Accepted: 13 March 2024Published: 14 March 2024Copyright: © 2024 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). International Journal of Molecular SciencesReviewClinical Insights into Structure, Regulation, and Targeting ofABL Kinases in Human LeukemiaAndrew Wu 1,2, Xiaohu Liu 1,2, Clark Fruhstorfer 1 and Xiaoyan Jiang 1,2,3,*1 Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia CancerResearch Institute, Vancouver, BC V5Z 1L3, Canada; awu@bccrc.ca (A.W.); wliu@virogin.com (X.L.)2 Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada3 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada* Correspondence: xjiang@bccrc.ca; Tel.: +604-675-8141Abstract: Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that origi-nates from a translocation event between chromosome 9 and chromosome 22 within the hematopoieticstem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosinekinase that can phosphorylate multiple downstream signaling molecules to promote cellular survivaland inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activityby preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However,disease relapses and the emergence of resistant clones have become a critical issue for CML therapeu-tics. Two main reasons behind the persisting obstacles to treatment are the a…
has type: Article
is shown at: 10.14288/1.0441472
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: Multidisciplinary Digital Publishing Institute
publisher DOI: 10.3390/ijms25063307
rights: CC BY 4.0
rights URI: https://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
scholar level: Researcher
subject: BCR::ABL1
subject: ABL regulation
subject: X-ray crystallographic structures
subject: chronic myeloid leukemia
subject: leukemia stem cell
subject: small-molecule inhibitors
subject: tyrosine kinase inhibitors
subject: TKI resistance
subject: BCR::ABL1 mutations
type: Text
identifier URI: http://hdl.handle.net/2429/87940