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FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation
BACKGROUND: BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. METHODS: In silico bioinformatic analysis was performed to i...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892744/ https://www.ncbi.nlm.nih.gov/pubmed/35241148 http://dx.doi.org/10.1186/s13046-022-02298-1 |
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author | Yang, Taewoo Sim, Kyu-Young Ko, Gwang-Hoon Ahn, Jae-Sook Kim, Hyeoung-Joon Park, Sung-Gyoo |
author_facet | Yang, Taewoo Sim, Kyu-Young Ko, Gwang-Hoon Ahn, Jae-Sook Kim, Hyeoung-Joon Park, Sung-Gyoo |
author_sort | Yang, Taewoo |
collection | PubMed |
description | BACKGROUND: BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. METHODS: In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. RESULTS: We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34(+) CML cells from patients with BCR-ABL-independent TKI-resistant disease. CONCLUSIONS: These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02298-1. |
format | Online Article Text |
id | pubmed-8892744 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88927442022-03-10 FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation Yang, Taewoo Sim, Kyu-Young Ko, Gwang-Hoon Ahn, Jae-Sook Kim, Hyeoung-Joon Park, Sung-Gyoo J Exp Clin Cancer Res Research BACKGROUND: BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. METHODS: In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. RESULTS: We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34(+) CML cells from patients with BCR-ABL-independent TKI-resistant disease. CONCLUSIONS: These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02298-1. BioMed Central 2022-03-03 /pmc/articles/PMC8892744/ /pubmed/35241148 http://dx.doi.org/10.1186/s13046-022-02298-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Yang, Taewoo Sim, Kyu-Young Ko, Gwang-Hoon Ahn, Jae-Sook Kim, Hyeoung-Joon Park, Sung-Gyoo FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title | FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title_full | FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title_fullStr | FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title_full_unstemmed | FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title_short | FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation |
title_sort | fam167a is a key molecule to induce bcr-abl-independent tki resistance in cml via noncanonical nf-κb signaling activation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892744/ https://www.ncbi.nlm.nih.gov/pubmed/35241148 http://dx.doi.org/10.1186/s13046-022-02298-1 |
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