Microenvironmental cell interactions are essential for sustaining functionality of myelofibrosis malignant stem cells

Area of Science:

• Hematology
• Cancer Biology
• Stem Cell Research

Background:

• Cancer progression is influenced by interactions between cancer stem cells (CSCs) and the tumor microenvironment (TME).
• Myelofibrosis (MF) is a stem cell-driven myeloproliferative neoplasm where CSCs interact with the TME.

Purpose of the Study:

• To develop a model for in vivo cancer stem cell/TME interactions.
• To investigate the functional consequences of malignant MF hematopoietic stem and progenitor cells (HSPCs) interacting with non-malignant TME cells (endothelial cells [ECs] and mesenchymal stromal cells [MSCs]).

Main Methods:

• Co-cultivation of MF HSPCs with normal donor ECs and MSCs to create a tri-culture system.
• Transplantation of co-cultured MF HSPCs into immunodeficient mice to assess MF phenotype recapitulation.
• Transcriptional profiling of co-cultured cells to identify molecular changes.

Main Results:

• The tri-culture system promoted malignant clone dominance and MF HSPC persistence.
• Co-cultured MF HSPCs recapitulated the MF phenotype, including splenomegaly and marrow fibrosis, upon transplantation.
• Transcriptional profiling revealed reprogramming of MF HSPCs, MSCs, and ECs, with a prominent upregulation of pro-inflammatory pathways.

Conclusions:

• This human multicellular model effectively demonstrates multidirectional interactions between MF HSPCs and TME cells.
• These interactions are essential for sustaining fully functional MF stem cells.
• The study highlights the critical role of the pro-inflammatory response in MF pathogenesis driven by CSC/TME interactions.