Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/127151
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Type: | Journal article |
Title: | RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses |
Author: | Adnan Awad, S. Dufva, O. Ianevski, A. Ghimire, B. Koski, J. Maliniemi, P. Thomson, D. Schreiber, A. Heckman, C.A. Koskenvesa, P. Korhonen, M. Porkka, K. Branford, S. Aittokallio, T. Kankainen, M. Mustjoki, S. |
Citation: | Leukemia, 2021; 35(4):1087-1099 |
Publisher: | Springer Nature |
Issue Date: | 2021 |
ISSN: | 0887-6924 1476-5551 |
Statement of Responsibility: | Shady Adnan Awad, Olli Dufva, Aleksandr Ianevski, Bishwa Ghimire, Jan Koski ... Susan Branford ... et al. |
Abstract: | Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1-/- and heterozygous RUNX1-/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients. |
Keywords: | Cell Line, Tumor Humans Blast Crisis Disease Susceptibility Combined Modality Therapy Flow Cytometry Immunophenotyping Signal Transduction Gene Deletion Binding Sites Protein Binding Drug Resistance, Neoplasm Phenotype Mutation Disease Management Core Binding Factor Alpha 2 Subunit Ikaros Transcription Factor Leukemia, Myelogenous, Chronic, BCR-ABL Positive Molecular Targeted Therapy Transcriptome Biomarkers, Tumor Gene Editing Exome Sequencing |
Description: | Published: 11 August 2020 |
Rights: | © The Author(s) 2020. This article is published with open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. |
DOI: | 10.1038/s41375-020-01011-5 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1104425 http://purl.org/au-research/grants/nhmrc/1117718 |
Published version: | http://dx.doi.org/10.1038/s41375-020-01011-5 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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hdl_127151.pdf | Published version | 3.1 MB | Adobe PDF | View/Open |
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