Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage
Abstract The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disea...
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BMC
2025-03-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00614-x |
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| author | Aurora Bernal Vincent Cuminetti Marc Serulla Adrian Florit Joanna Konieczny Golnaz Golnarnik Yimeng Chen Marc Ferré Samuel Geiseler Anders Vik Randi Olsen Lorena Arranz |
| author_facet | Aurora Bernal Vincent Cuminetti Marc Serulla Adrian Florit Joanna Konieczny Golnaz Golnarnik Yimeng Chen Marc Ferré Samuel Geiseler Anders Vik Randi Olsen Lorena Arranz |
| author_sort | Aurora Bernal |
| collection | DOAJ |
| description | Abstract The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2 V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9 + acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3–6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2 V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin+ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS G12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRAS G12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRAS G12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients. |
| format | Article |
| id | doaj-art-7a7760090a8245bdacff0aa67a705523 |
| institution | DOAJ |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-7a7760090a8245bdacff0aa67a7055232025-08-20T03:06:00ZengBMCExperimental Hematology & Oncology2162-36192025-03-011411910.1186/s40164-025-00614-xBone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damageAurora Bernal0Vincent Cuminetti1Marc Serulla2Adrian Florit3Joanna Konieczny4Golnaz Golnarnik5Yimeng Chen6Marc Ferré7Samuel Geiseler8Anders Vik9Randi Olsen10Lorena Arranz11Stem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Centre of Embryology and Healthy Development, Institute of Clinical Medicine, Faculty of Medicine, University of OsloStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Hematology, University Hospital of North NorwayAdvanced Microscopy Core Facility, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayStem Cells, Ageing and Cancer Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayAbstract The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2 V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9 + acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3–6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2 V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin+ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS G12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRAS G12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRAS G12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.https://doi.org/10.1186/s40164-025-00614-xStem cell nicheHematological cancersPeripheral nervous systemSympathetic fibresTransmission electron microscopy |
| spellingShingle | Aurora Bernal Vincent Cuminetti Marc Serulla Adrian Florit Joanna Konieczny Golnaz Golnarnik Yimeng Chen Marc Ferré Samuel Geiseler Anders Vik Randi Olsen Lorena Arranz Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage Experimental Hematology & Oncology Stem cell niche Hematological cancers Peripheral nervous system Sympathetic fibres Transmission electron microscopy |
| title | Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| title_full | Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| title_fullStr | Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| title_full_unstemmed | Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| title_short | Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| title_sort | bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage |
| topic | Stem cell niche Hematological cancers Peripheral nervous system Sympathetic fibres Transmission electron microscopy |
| url | https://doi.org/10.1186/s40164-025-00614-x |
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