The following is a summary of the “Establishment of isogenic induced pluripotent stem cells with or without pathogenic mutation for understanding the pathogenesis of myeloproliferative neoplasms,” published in the February 2023 issue of Hematology by Liu, et al.

Understanding the pathophysiology of hematologic malignancies relies heavily on the identification and functional characterization of disease-associated genetic features. To further investigate these genetic modifications, numerous in vitro and in vivo models have been developed using cell lines, primary cells, and animal models. Data interpretation is sometimes constrained by their nonphysiological settings, varied genetic origins, and species-specific variances. 

To assess the impact of somatic mutations in myeloproliferative neoplasms (MPNs), we created isogenic induced pluripotent stem (iPS) cell lines with and without the JAK2V617F mutation, a driving mutation of MPNs, using CRISPR/Cas9 in combination with the piggyBac transposon system. They used these iPS cells to produce hematopoietic stem/progenitor cells (HSPCs), and then used fluorescence-activated cell sorting techniques to observe phenotypic variations throughout hematopoiesis. 

The cell-autonomous erythropoiesis and megakaryopoiesis seen in the bone marrow of MPN patients can also be observed in HSPCs with pathogenic mutations.  They also demonstrated that interferon alpha specifically inhibited erythropoiesis and megakaryopoiesis in mutant HSPCs while using this cell type as a model to validate medicinal drugs. These findings prove the viability of genome editing in the context of creating isogenic iPS cells, analysing genetic components to better understand the pathophysiology of MPNs, and testing medicinal molecules for use against MPNs.