Melatonin nanoparticles inhibit mutant hematopoiesis and restore bone marrow architecture in myeloproliferative neoplasms
- 1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
Abstract
Myeloproliferative neoplasms (MPN) are chronic hematologic malignancies characterized by clonal myeloid expansion, inflammation, oxidative stress, and progressive bone marrow (BM) remodeling that may culminate in fibrosis and secondary acute leukemia. Here, we evaluated the therapeutic efficacy and the underlying mechanisms of melatonin (MT) and liposomal melatonin (nano-MT) in preclinical MPN models. MT selectively inhibited clonogenic growth of patient-derived peripheral blood mononuclear cells and induced pluripotent stem cell-derived CD34 hematopoietic stem and progenitor cells in comparison to healthy controls. This effect was associated with increased apoptosis, reduced reactive oxygen species (ROS), and decreased glucose uptake, independently of MT receptor signaling. Transcriptomic profiling of primary MPN CD34 cells revealed suppression of MYC targets, G2M checkpoint signaling, ROS, and glycolysis pathways. In co-culture models, MT reduced stromal -smooth muscle actin and phosphorylated SMAD2/3, indicating inhibition of TGF-{beta}-driven mesenchymal stromal cell-to-myofibroblast formation. In tamoxifen-inducible SclCreER;JAK2V617F mice, nano-MT achieved efficient spleen and BM targeting. Therapeutically, nano-MT reduced erythrocytosis, myeloid progenitor expansion, and BM IL-1{beta} levels. Longitudinal micro-computed tomography and histological analyses demonstrated normalization of BM architecture, reduced osteosclerotic remodeling and splenomegaly, decreased reticulin deposition and megakaryocyte numbers. In a dose-escalation study, nano-MT restored erythrocyte, hematocrit, and platelet counts and normalized megakaryocyte-erythroid progenitors. Combination treatment with ruxolitinib further reduced leukocytosis, neutrophilia, and monocytosis. Collectively, these findings demonstrate that (nano-)MT attenuates MPN and BM remodeling by targeting metabolic, inflammatory, and fibrotic pathways. This study provides the first evidence for a therapeutic benefit of nano-MT in MPN and establishes a rationale for further translational evaluation.
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BibTeX
@misc{gupta2026melatonin,
title = {{Melatonin nanoparticles inhibit mutant hematopoiesis and restore bone marrow architecture in myeloproliferative neoplasms}},
author = {S. Gupta and A. Motta and S. Elsafy and S. Khorshid and A. Nucci and V. Sampath and A. Bhattacharjee and M. Vieri and K. Olschok and K. Pannen and J. Lazarevic and M. J. Rodriguez and P. Weiand and V. Hariharan and C. B. Lopez and C. Zhou and H. Jacobi and B. Junge and T. N. Rao and F. Kiessling and E. P. C. van der Vorst and T. Lammers and F. De Lorenzi and J. Baumeister and S. Koschmieder and M. A. Szymanski de Toledo and A. M. Sofias and N. Chatain},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.746520},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.746520v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Melatonin nanoparticles inhibit mutant hematopoiesis and restore bone marrow architecture in myeloproliferative neoplasms
AU - S. Gupta
AU - A. Motta
AU - S. Elsafy
AU - S. Khorshid
AU - A. Nucci
AU - V. Sampath
AU - A. Bhattacharjee
AU - M. Vieri
AU - K. Olschok
AU - K. Pannen
AU - J. Lazarevic
AU - M. J. Rodriguez
AU - P. Weiand
AU - V. Hariharan
AU - C. B. Lopez
AU - C. Zhou
AU - H. Jacobi
AU - B. Junge
AU - T. N. Rao
AU - F. Kiessling
AU - E. P. C. van der Vorst
AU - T. Lammers
AU - F. De Lorenzi
AU - J. Baumeister
AU - S. Koschmieder
AU - M. A. Szymanski de Toledo
AU - A. M. Sofias
AU - N. Chatain
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.746520
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.746520v1
AB - Myeloproliferative neoplasms (MPN) are chronic hematologic malignancies characterized by clonal myeloid expansion, inflammation, oxidative stress, and progressive bone marrow (BM) remodeling that may culminate in fibrosis and secondary acute leukemia. Here, we evaluated the therapeutic efficacy and the underlying mechanisms of melatonin (MT) and liposomal melatonin (nano-MT) in preclinical MPN models. MT selectively inhibited clonogenic growth of patient-derived peripheral blood mononuclear cells and induced pluripotent stem cell-derived CD34 hematopoietic stem and progenitor cells in comparison to healthy controls. This effect was associated with increased apoptosis, reduced reactive oxygen species (ROS), and decreased glucose uptake, independently of MT receptor signaling. Transcriptomic profiling of primary MPN CD34 cells revealed suppression of MYC targets, G2M checkpoint signaling, ROS, and glycolysis pathways. In co-culture models, MT reduced stromal -smooth muscle actin and phosphorylated SMAD2/3, indicating inhibition of TGF-{beta}-driven mesenchymal stromal cell-to-myofibroblast formation. In tamoxifen-inducible SclCreER;JAK2V617F mice, nano-MT achieved efficient spleen and BM targeting. Therapeutically, nano-MT reduced erythrocytosis, myeloid progenitor expansion, and BM IL-1{beta} levels. Longitudinal micro-computed tomography and histological analyses demonstrated normalization of BM architecture, reduced osteosclerotic remodeling and splenomegaly, decreased reticulin deposition and megakaryocyte numbers. In a dose-escalation study, nano-MT restored erythrocyte, hematocrit, and platelet counts and normalized megakaryocyte-erythroid progenitors. Combination treatment with ruxolitinib further reduced leukocytosis, neutrophilia, and monocytosis. Collectively, these findings demonstrate that (nano-)MT attenuates MPN and BM remodeling by targeting metabolic, inflammatory, and fibrotic pathways. This study provides the first evidence for a therapeutic benefit of nano-MT in MPN and establishes a rationale for further translational evaluation.
ER -