Basophilic Erythroblast Emerges as the Key Turning Point in Polycythemia Vera
Abstract Polycythemia vera (PV) is a rare, chronic myeloproliferative neoplasm driven by the JAK2V617F mutation and characterized by uncontrolled erythroid proliferation. Although the mutation arises in hematopoietic stem cells, the differentiation stage at which its transcriptional consequences first become biologically meaningful has remained undefined. Using a multi-layer transcriptomics…
Polycythemia vera (PV) is a rare, chronic myeloproliferative neoplasm driven by a mutated JAK2V617F gene. This mutation causes uncontrolled erythroid proliferation, but the stage at which the mutation becomes biologically significant has been unclear. Researchers used multiple transcriptomics techniques on single-cell RNA sequencing data to uncover the critical turning point in PV.
They found that basophilic erythroblasts, a specific stage of erythroid development, mark the transition when JAK2V617F shifts from being present but inactive to actively altering gene expression and driving the disease. At this stage, the disease exhibits unique signatures, such as iron regulation through ERFE, RAS/MAPK co-activation via MAP2K2, and epigenetic changes.
Additionally, the environment surrounding these cells underwent remodeling, marked by TGF{beta} signaling and chemokine production. Pseudotime analysis revealed that these basophilic erythroblasts were the first erythroid cells to diverge in their developmental trajectory, despite carrying the mutation. Interferon treatment showed the most significant impact at this stage, indicating that basophilic erythroblasts are both the primary therapeutic target and the point of greatest vulnerability in PV.
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