Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy

Autor: Bing Chen, Yan Lu, Xiangyu Ge, Pingping Shen, Shiman Zuo, Jingyue Wang, Yuxin Wang, Luchen Sun, Nanfei Yang
Rok vydání: 2021
Předmět:
Acute promyelocytic leukemia
Cancer Research
Cellular differentiation
Immunology
Mice
Nude
Mesenchymal Stem Cell Transplantation
Benzoates
Article
Thrombopoiesis
Umbilical Cord
Cellular and Molecular Neuroscience
Differentiation therapy
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
hemic and lymphatic diseases
medicine
Animals
Humans
Cell Lineage
lcsh:QH573-671
Progenitor cell
neoplasms
Chronic myeloid leukaemia
Janus Kinases
Thrombopoietin receptor
lcsh:Cytology
Gene Expression Regulation
Leukemic
business.industry
Myeloid leukemia
Mesenchymal Stem Cells
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
Coculture Techniques
STAT Transcription Factors
Leukemia
Haematopoiesis
Hydrazines
Cancer research
Pyrazoles
Mitogen-Activated Protein Kinases
K562 Cells
business
Receptors
Thrombopoietin
Signal Transduction
Zdroj: Cell Death & Disease
Cell Death and Disease, Vol 12, Iss 2, Pp 1-15 (2021)
ISSN: 2041-4889
DOI: 10.1038/s41419-021-03499-w
Popis: Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.
Databáze: OpenAIRE
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