PUBLICATION
Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl)
- Authors
- Meng, P., Liu, W., Lao, J., Liu, X., Zhang, Y., Sun, Y., Zhou, R., Du, C., Wang, J., Zhao, D., Lin, Q., Zhang, Y.
- ID
- ZDB-PUB-240923-5
- Date
- 2024
- Source
- Journal of thrombosis and haemostasis : JTH 22(12): 3599-3613 (Journal)
- Registered Authors
- Lin, Qing, Zhang, Yangping, Zhang, Yiyue, Zhou, Riyang
- Keywords
- MPL, Paclitaxel, Platelet, Thrombocyte, Zebrafish
- MeSH Terms
-
- Phenotype
- Janus Kinase 2/genetics
- Janus Kinase 2/metabolism
- Zebrafish*
- Animals
- Animals, Genetically Modified
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Receptors, Thrombopoietin*/metabolism
- Paclitaxel*/pharmacology
- Thrombopoiesis*/drug effects
- Mice, Inbred C57BL
- Mice
- Signal Transduction
- Thrombocytopenia/blood
- Thrombocytopenia/chemically induced
- Cell Proliferation/drug effects
- Blood Platelets*/drug effects
- Blood Platelets*/metabolism
- Megakaryocytes/drug effects
- Megakaryocytes/metabolism
- PubMed
- 39307245 Full text @ J. Thromb. Haemost.
Citation
Meng, P., Liu, W., Lao, J., Liu, X., Zhang, Y., Sun, Y., Zhou, R., Du, C., Wang, J., Zhao, D., Lin, Q., Zhang, Y. (2024) Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl). Journal of thrombosis and haemostasis : JTH. 22(12):3599-3613.
Abstract
Background Platelets are critical for thrombosis and hemostasis. The TPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration.
Objectives We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering bypassed TPO-MPL pathways.
Methods We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify FDA-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. The BrdU, TUNEL, and RNA-Seq analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes.
Results We found that paclitaxel is able to expand thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish, and elevates platelet levels in mice. This effect occurs bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis.
Conclusion Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the Jak2-Erk1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping