| 1. |
- Cai, Huan, et al.
(author)
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Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression
- 2022
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:20, s. 3040-3057
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Journal article (peer-reviewed)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.
(author)
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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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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Journal article (peer-reviewed)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.
(author)
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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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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Journal article (peer-reviewed)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. |
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| 5. |
- Rudd, Sean, et al.
(author)
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Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy
- 2020
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In: EMBO Molecular Medicine. - : Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684.
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Journal article (peer-reviewed)abstract
- The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML. © 2020 The Authors. Published under the terms of the CC BY 4.0 license
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| 6. |
- Sandhow, Lakshmi
(author)
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Mesenchymal niche contribution to normal and malignant hematopoiesis
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Normal hematopoiesis is tightly regulated by hematopoietic microenvironment/niche in bone marrow (BM) via direct hematopoietic cell-niche cell interaction and factors secreted by various types of cellular niches. The BM niche consists of cells of mesenchymal cell origin including mesenchymal stem cells (MSCs) and progenitor cells (MPCs). Accumulated evidence suggests the important role of BM mesenchymal cell niche for the maintenance of normal hematopoiesis and leukemogenesis. However, the exact role of different niche elements and the molecular mechanisms in leukemia development remain poorly defined. Knowledge is required for developing new therapeutic strategy to effectively treat the diseases. This thesis focuses on mesenchymal niche contribution to normal and malignant hematopoiesis, particularly, myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). By using mouse models, multi-color flow cytometry, RNA-sequencing, transplantation and lineage tracing techniques, the thesis work has demonstrated the contribution of BM mesenchymal cell niche in the initiation of the myeloproliferative disease and progression of AML. The specific role of BM MSCs and laminin isoforms in AML progression and therapy response were studied. In addition, this thesis reports the features of native skin MSCs and their function in supporting normal hematopoietic and AML stem cells. In paper I, the instructive role of BM niches in MDS/MPN initiation is studied by using signalinduced proliferation associated 1 (Sipa1) gene deleted mice (Sipa1-/-) that develop agedependent MPN. The loss of Sipa1 induces BM niche alterations prior to the disease onset, including biased differentiation of Sipa1-/- MSCs towards adipocytes and upregulated expression of pro-inflammatory genes (Il-6 and TGF-β). Concomitantly, hematopoiesis maintenance gene (Cxcl12, Angptl1, Kitl) expressions were reduced in Sipa1-/- BM MSCs and MPCs. Transplantation of Sipa1+/+ hematopoietic cells to young Sipa1-/- mice resulted in MDS/MPN development, supporting the causative role of Sipa1 deficient niche for the development of MDS/MPN. The role of BM MSCs and MPCs during progression of AML is reported in paper II. By transplanting MLL-AF9+ AML cells to immunocompetent mice, we showed dynamic niche alterations induced by AML cells. During AML development, frequency of BM MSC & MPC were increased while hematopoiesis gene (Kitl, Cxcl12, Angptl1, Nov and Igf1) expression in BM MPCs were down regulated in correlation to AML engraftment in BM. Moreover, the expression of pro-inflammatory gene (Il-6) is elevated following the AML progression. Specifically, BM primitive subset of MSC (Ebf2+) is altered by AML cells to generate more progenies including Ebf2-MSC, MPC and CD44+ cells in the leukemic niche. The depletion of Ebf2+ cells accelerated AML development, demonstrating the suppressive role of Ebf2+ MSCs in AML progression possibly by maintaining normal hematopoiesis. In this study, upregulation of laminin 4 (Lama4) in both MSC and MPC was observed. To further investigate the functional consequence of Lama4 during AML development, the Lama4 (Lama4-/-) deficient mice were employed in paper III. We firstly studied the role of Lama4 in hematopoiesis regeneration following irradiationinduced stress and observed impaired recovery of erythropoiesis and megakaryopoiesis in Lama4-/- mice. On the contrary, AML progression and relapse were accelerated post transplantation of MLL-AF9+ AML cells. Furthermore, the Lama4-/- MSCs promoted AML cell growth and confer AML stem cell chemoresistance to cytarabine (Ara-C) via providing more metabolic support to the AML stem cells (LSCs). Taken together, paper III shows critical role of Lama4 in hematopoiesis recovery following irradiation and during AML development. Recent study has shown that AML LSCs infiltrate extramedullary organ. Meanwhile, skin has been reported to contain MSC-like population although the characteristics are not well defined. In paper IV, we employed Ebf2-gfp transgenic mice to prospectively characterize skin MSC phenotypically and functionally at bulk and single cell level. Skin Ebf2+ cells represent purified MSC while the Ebf2-fraction contained more differentiated MSCs that can be generated by the Ebf2+ cells, revealed by the in vivo lineage tracing of Ebf2+ MSCs. Both skin Ebf2+ cells and Ebf2-MSC displayed hematopoiesis supportive function, similar to their BM counterpart. Furthermore, co-culture of AML and AML CAFC on skin Ebf2+ and Ebf2-MSCs showed that skin MSCs also supported normal HSCs and provided chemoprotection for AML LSCs. In skin tissue of AML mice, infiltration of AML cells was observed and remained in skin tissue after Ara-C treatment, suggesting a possible contribution of skin MSCs to the persistence of AML cells. The skin Ebf2+ were found to be reduced in AML mice. However, the functional consequence of the skin MSCs remains to be investigated in the future. Altogether, paper IV reports skin harbors Ebf2+ and Ebf2-MSC with similar characteristics to BM MSC. Both skin Ebf2+ and Ebf2-MSCs support normal HSC and AML cells. Importantly, skin MSCs provide chemoprotection for AML LSC. In conclusion, the work in this thesis shows the role of BM niche for the initiation and progression of the myeloid malignancies using several transgenic mouse models. The work also provides evidence for critical role of Lama4 in hematopoiesis recovery following irradiation and AML progression. Furthermore, the biological features of skin MSCs and their function in supporting normal hematopoietic and AML cells. During Ara-C treatment, skin MSCs also displayed protective role for AML LSCs, indicating skin MSC possible role as a reservoir of chemoresistant AML LSC.
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| 7. |
- Sandhow, Lakshmi, et al.
(author)
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Skin mesenchymal niches maintain and protect AML-initiating stem cells
- 2023
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In: Journal of Experimental Medicine. - 0022-1007 .- 1540-9538. ; 220:10
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Journal article (peer-reviewed)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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