| 1. |
- Cai, Huan, et al.
(författare)
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Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:20, s. 3040-3057
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of normal hematopoiesis and leukemia progression are 2 well-linked processes during leukemia development and are controlled by the bone marrow (BM) niche. Extracellular matrix proteins, including laminin, are important BM niche components. However, their role in hematopoiesis regeneration and leukemia is unknown. Laminin α4 (Lama4), a major receptor-binding chain of several laminins, is altered in BM niches in mice with acute myeloid leukemia (AML). So far, the impact of Lama4 on leukemia progression remains unknown. We here report that Lama4 deletion in mice resulted in impaired hematopoiesis regeneration following irradiation-induced stress, which is accompanied by altered BM niche composition and inflammation. Importantly, in a transplantation-induced MLL-AF9 AML mouse model, we demonstrate accelerated AML progression and relapse in Lama4−/− mice. Upon AML exposure, Lama4−/− mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations, including upregulation of inflammatory cytokines that favor AML growth. Lama4−/− MSCs displayed increased antioxidant activities and promoted AML stem cell proliferation and chemoresistance to cytarabine, which was accompanied by increased mitochondrial transfer from the MSCs to AML cells and reduced reactive oxygen species in AML cells in vitro. Similarly, we detected lower levels of reactive oxygen species in AML cells from Lama4−/− mice post–cytarabine treatment. Notably, LAMA4 inhibition or knockdown in human MSCs promoted human AML cell proliferation and chemoprotection. Together, our study for the first time demonstrates the critical role of Lama4 in impeding AML progression and chemoresistance. Targeting Lama4 signaling pathways may offer potential new therapeutic options for AML.
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| 2. |
- Dolinska, Monika, et al.
(författare)
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Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Tidskriftsartikel (refereegranskat)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. 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.
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| 3. |
- Dolinska, Monika, et al.
(författare)
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Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Tidskriftsartikel (refereegranskat)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. 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.
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| 4. |
- Dolinska, Monika, et al.
(författare)
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Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34+CD38- stem and progenitor cells in chronic myeloid leukemia
- 2017
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 490:2, s. 378-384
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL+CD34+CD38- cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34+CD38- cells from 7 CML patients. The majority of the single leukemic BCR-ABL +CD34+CD38- cells expressed cysteinyl leukotriene receptors CYSLT1 and CYSLT2. However, montelukast, an inhibitor of CYSLT1, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLT1 signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients.
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| 5. |
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| 6. |
- Sandhow, Lakshmi, et al.
(författare)
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Skin mesenchymal niches maintain and protect AML-initiating stem cells
- 2023
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Ingår i: Journal of Experimental Medicine. - 0022-1007 .- 1540-9538. ; 220:10
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Tidskriftsartikel (refereegranskat)abstract
- Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.
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| 7. |
- Xiao, Pingnan
(författare)
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Bone marrow mesenchymal stem and progenitor cells in myeloid malignancies
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hematopoietic stem cells (HSCs) reside in bone marrow (BM) microenvironment / niche to self-renew and generate all types of mature blood cells in postnatal life. This process is called hematopoiesis. Normal hematopoiesis is tightly regulated by both intrinsic signaling in HSCs and extrinsic signals from BM niche. Despite the involvement of BM niche in normal and malignant hematopoiesis has been reported, how different BM cellular niche contribute to leukemia progression and how leukemia cells affect their BM niche remain largely unknown. The overall aim of this thesis was to determine the roles of BM niche cells in the regulation of different myeloid malignancies, and understand the underlying mechanisms. In study I, by taking advantage of Sipa1-/- mouse model, we revealed that the loss of Sipa1 in mice led to BM niche alterations before the onset of MDS/MPN, and confirmed that the loss of Sipa1 in BM niche, but not in hematopoietic cells led to the MDS/MPN. Moreover, we detected abnormal inflammatory cytokines and growth factors in the BM stromal cells of the disease-free young adult Sipa1-/- mice, which could contribute to the pathogenesis of the MDS/MPN in aged Sipa1-/- mice. This study provides evidence for BM niche-induced MDS/MPN and the underlying molecular and cellular mechanisms. Given the distinct pathogenesis of different types of myeloid malignancies, we further investigated the contributions of BM niche to AML progression using MLL-AF9+ AML mouse model in study II. We detected alterations of BM niche cells in symptomatic AML mice, and confirmed similar alterations of BM stromal cells in the NSG mice engrafted with primary patient AML cells. Furthermore, BM niche cells in the AML mice produced altered growth factors, cytokines, and matrix proteins. Dynamic BM niche cell analysis and gene expression assay revealed that the BM niche alterations correlated with AML burden. We next functionally determined the roles of BM MSCs marked by Ebf2 expression in AML progression. We demonstrated that the Ebf2+ cells participated in AML BM niche formation. Notably, the depletion of Ebf2+ cells accelerated AML development in mice, indicating the suppressive roles of native BM niche to AML development. This study indicated that AML cells educated normal BM niche into a reinforcing AML BM niche contributing to AML progression. In study III, we found that BM MSCs altered their phenotype with reduced SCA1 expression in non-adherent culture, emphasizing culture-related alterations of BM MSC immunophenotype. In study IV, by using LTC-IC assay and single cell PCR, we revealed diverse expressions of leukotriene signaling molecules and minor effects of ALOX5 and CYSLT1 antagonists on CML LSC growth, particularly in the presence of BM stromal cells in vitro. All together, we phenotypically, molecularly, and functionally characterized leukemic BM niche and determined the niche contributions to different myeloid malignancies. Targeting on BM niche factors or restore BM niche components might be new therapeutic strategies for these myeloid malignancies.
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