| 1. |
- 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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| 2. |
- 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
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
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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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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| 4. |
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| 5. |
- Dolinska, Monika
(författare)
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Understanding the role of bone marrow niche in myeloid malignancies
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Normal hematopoiesis is generated and maintained by rare hematopoietic stem cells (HSCs) through their capacity to self-renew and differentiate. This process is rigorously controlled, both by HSC-intrinsic molecular programs and extrinsic signals emitted by the local bone marrow (BM) microenvironment, the so-called HSC niche. The BM niche consists of many cellular elements, including mesenchymal stem cells (MSCs), and soluble factors secreted by the cells. The niche homeostasis is critical for maintenance of normal hematopoiesis, and disruption of this BM niche may lead to malignant hematopoiesis, including leukemia. On the other hand, once malignant hematopoiesis is established, the niche structure and composition can be altered to protect leukemia-initiating stem cell (LSC). The aims of the presented thesis were to investigate the role of the BM niche in development of myeloid malignancies. In study I, we analyzed expression of leukotriene (LT) signaling molecules in LSCs derived from chronic myeloid leukemia (CML) patients, and tested their response to pharmacological inhibition of LT signaling. By using single cell PCR, we found only low expression of ALOX5 in patient BCR-ABL+ LSCs and BCR-ABL- HSCs. Moreover, in contrast to previous observations in mice and in liquid cultures in vitro, pharmacological inhibition of ALOX5 did not result in any significant growth suppression of CML LSCs in long-term culture initiating cell (LTC-IC) assay on a stromal cell layer. Furthermore, although expression of CYSLT1 was detected in the majority of analyzed LSCs, treatment with its antagonist, montelukast, did not significantly reduce the LTC-IC activity of LSCs. Thus, these results suggest that pharmacological inhibition of the LT pathway might not be sufficient to eradicate LSCs, particularly in the presence of BM stromal cells. In study II, we investigated the role of BM niche in pathogenesis of MDS/MPN by using a Sipa1-/- mouse model. We found that Sipa1 was expressed in BM stromal cells from mice and healthy humans, but was downregulated in these cells from patients with MPN and MDS/MPN. Additionally, Sipa1 deficiency in mice led to phenotypical and functional alterations in the BM cellular niche prior to disease development, and reciprocal transplantation experiments further confirmed that Sipa1-/- BM niche was a prerequisite for MDS/MPN development. Moreover, RNA sequencing analysis showed dysregulated expression of inflammatory cytokines and growth factors in the BM stromal cells from young, disease-free Sipa1-/- mice. Altogether, our data suggest that Sipa1 expression in the BM stromal cells is critical for maintaining BM niche homeostasis, and that Sipa1 deficiency in BM niche plays an instructive role in development of MDS/MPN in mice. Finally in study III, we prospectively characterized BM stromal cells in newly-diagnosed patients with CML. First of all, we discovered that patient’s BM stromal cells share similar immunophenotype as normal BM (NBM) counterparts, but that the CML BM niche composition was changed, showing increased frequency of endothelial cells. Moreover, we found alterations in functional properties of CML-derived MSCs, e.g. an impaired osteochondrogenic differentiation potential, and an enhanced capacity to support NBM hematopoietic stem and progenitor cells in vitro. Even though no BCR-ABL fusion gene was detected in CML BM stromal cells, the RNA sequencing revealed cytokine dysregulation, particularly loss of CXCL14 in CML BM niche. Interestingly, restoration of CXCL14 expression in stromal cells suppressed the growth of LSCs in LTC-IC assays, but promoted their differentiation. These results indicate that CXCL14 might help to eradicate LSCs and therefore serve as a new therapeutic candidate for CML treatment. To conclude, we herein showed that BM niche might contribute to myeloid malignancies in mice and human. Thus, targeting the dysregulated BM niche factors and the abnormal interaction between BM niche and LSCs could be a promising therapeutic approach to treat patients with myeloid malignancies.
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| 6. |
- Yektaei-Karin, Elham, et al.
(författare)
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Modulation of leukotriene signaling inhibiting cell growth in chronic myeloid leukemia
- 2017
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 58:8, s. 1903-1913
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Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) have dramatically improved clinical outcome in chronic myeloid leukemia (CML), cure rarely occurs. This may be due to BCR-ABL-independent, aberrant signaling pathways, one of which leads to leukotriene (LT) formation. Well-recognized as inflammatory mediators, LT can also affect oncogenic mechanisms of several tumors. We have previously discovered elevated LT-synthesis and up-regulated cysteinyl-LT-inducing enzyme in CML. Here we report on dose-dependent inhibition of CML cell growth exerted by specific blockers of LT-signaling. Thus, the cysteinyl-LT1-receptor-antagonist montelukast significantly reduced the growth of K562, KCL22, and KU812 cells, as well as primary CD34(+) blood cells from two CML patients. Adding montelukast to the TKI imatinib caused combined inhibition. No effect was seen on normal bone marrow cells. Similarly, growth inhibition was also observed with the 5-lipoxygenase (LO)-inhibitor BWA4C, the 5-LO-activating-protein-(FLAP)-inhibitor licofelone and the LTB4(BLT1)-receptor-antagonist LY293111. Thus, blocking of aberrant LT-signaling may provide an additional, novel therapeutic possibility in CML.
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