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Characterization of...
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
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- Dolinska, Monika (author)
- Karolinska Institute, Stockholm, Sweden
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- Cai, Huan (author)
- Karolinska Institute, Stockholm, Sweden
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- Mansson, Alma (author)
- Karolinska Institute, Stockholm, Quebec, Sweden
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- Shen, Jingyi (author)
- Karolinska Institute, Stockholm, Sweden
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- Xiao, Pingnan (author)
- Karolinska Institute, Stockholm, Sweden
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- Bouderlique, Thibault (author)
- Karolinska, Sweden
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- Li, Xidan (author)
- Karolinska Institute, Stockholm, Alabama, Sweden
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- Leonard, Elory (author)
- Karolinska Institute, Stockholm, Sweden
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- Chang, Marcus (author)
- Karolinska Institute, Stockholm, Sweden
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- Gao, Yuchen (author)
- Karolinska Institute, Stockholm, Sweden
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- Medina Giménez, Juan Pablo (author)
- Karolinska Institute, Stockholm, Sweden
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- Kondo, Makoto (author)
- Karolinska, Sweden
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- Sandhow, Lakshmi (author)
- Karolinska Institute, Stockholm, Sweden
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- Johansson, Anne-Sofie (author)
- Karolinska Institutet, Huddinge, Sweden
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- Deneberg, Stefan (author)
- Karolinska University Hospital, Huddinge, Stockholm, Sweden
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- Söderlund, Stina (author)
- Uppsala University Hospital
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- Jädersten, Martin (author)
- Karolinska Institutet, Stockholm, Sweden
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- Ungerstedt, Johanna S (author)
- Karolinska Institutet and Karolinska University Hospital, Stockholm, Armenia
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- Tobiasson, Magnus (author)
- Karolinska Institute, Stockholm, Sweden
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- Östman, Arne (author)
- Karolinska Institute, Stockholm, Sweden
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- Mustjoki, Satu (author)
- University of Helsinki, Helsinki, Finland
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- Stenke, Leif (author)
- Dept of Hematology, Stockholm, Sweden
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- Le Blanc, Katarina (author)
- Karolinska Institutet, Stockholm, Sweden
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- Hellstrom-Lindberg, Eva S (author)
- Karolinska Institutet, Stockholm, Sweden
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- Lehmann, Sören (author)
- Karolinska, Sweden
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- Ekblom, Marja (author)
- Lund Stem Cell Center, Lund, Sweden
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- Olsson-Strömberg, Ulla (author)
- University Hospital, Uppsala, Sweden
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- Sigvardsson, Mikael, 1965- (author)
- Linköpings universitet,Medicinska fakulteten,Avdelningen för molekylär medicin och virologi,Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
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- Qian, Hong (author)
- Karolinska Institute, Stockholm, Sweden
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(creator_code:org_t)
- American Society of Hematology, 2023
- 2023
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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https://urn.kb.se/re...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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Blood
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To the university's database
- By the author/editor
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Dolinska, Monika
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Cai, Huan
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Mansson, Alma
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Shen, Jingyi
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Xiao, Pingnan
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Bouderlique, Thi ...
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show more...
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Li, Xidan
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Leonard, Elory
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Chang, Marcus
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Gao, Yuchen
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Medina Giménez, ...
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Kondo, Makoto
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Sandhow, Lakshmi
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Johansson, Anne- ...
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Deneberg, Stefan
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Söderlund, Stina
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Jädersten, Marti ...
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Ungerstedt, Joha ...
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Tobiasson, Magnu ...
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Östman, Arne
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Mustjoki, Satu
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Stenke, Leif
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Le Blanc, Katari ...
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Hellstrom-Lindbe ...
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Lehmann, Sören
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Ekblom, Marja
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Olsson-Strömberg ...
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Sigvardsson, Mik ...
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Qian, Hong
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Blood
- By the university
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Linköping University