Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
(2023) In Blood 142(1). p.73-89- Abstract
Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38– cells.... (More)
Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38– cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
(Less)
- author
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 142
- issue
- 1
- pages
- 17 pages
- publisher
- American Society of Hematology
- external identifiers
-
- pmid:37018663
- scopus:85163377077
- ISSN
- 0006-4971
- DOI
- 10.1182/blood.2022016896
- language
- English
- LU publication?
- yes
- id
- 97855a0c-7bbd-4a3b-a53c-5d7e26c919c9
- date added to LUP
- 2023-09-05 14:18:15
- date last changed
- 2024-06-15 07:56:13
@article{97855a0c-7bbd-4a3b-a53c-5d7e26c919c9,
abstract = {{<p>Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34<sup>+</sup>CD38<sup>–</sup> cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.</p>}},
author = {{Dolinska, Monika and Cai, Huan and Månsson, Alma and Shen, Jingyi and Xiao, Pingnan and Bouderlique, Thibault and Li, Xidan and Leonard, Elory and Chang, Marcus and Gao, Yuchen and Medina, Juan Pablo and Kondo, Makoto and Sandhow, Lakshmi and Johansson, Anne Sofie and Deneberg, Stefan and Söderlund, Stina and Jädersten, Martin and Ungerstedt, Johanna and Tobiasson, Magnus and Östman, Arne and Mustjoki, Satu and Stenke, Leif and Le Blanc, Katarina and Hellström-Lindberg, Eva and Lehmann, Sören and Ekblom, Marja and Olsson-Strömberg, Ulla and Sigvardsson, Mikael and Qian, Hong}},
issn = {{0006-4971}},
language = {{eng}},
number = {{1}},
pages = {{73--89}},
publisher = {{American Society of Hematology}},
series = {{Blood}},
title = {{Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option}},
url = {{http://dx.doi.org/10.1182/blood.2022016896}},
doi = {{10.1182/blood.2022016896}},
volume = {{142}},
year = {{2023}},
}