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Cerebral cavernous malformation (CCM) is a neurovascular disease that can lead to seizures and stroke-like symptoms. The familial form is caused by a heterozygous germline mutation in either the <i>CCM1</i>, <i>CCM2,</i> or <i>CCM3</i> gene. While the importance of a second-hit mechanism in CCM development is well established, it is still unclear whether it immediately triggers CCM development or whether additional external factors are required. We here used RNA sequencing to study differential gene expression in <i>CCM1</i> knockout induced pluripotent stem cells (<i>CCM1</i>^−/− iPSCs), early mesoderm progenitor cells (eMPCs), and endothelial-like cells (ECs). Notably, CRISPR/Cas9-mediated inactivation of <i>CCM1</i> led to hardly any gene expression differences in iPSCs and eMPCs. However, after differentiation into ECs, we found the significant deregulation of signaling pathways well known to be involved in CCM pathogenesis. These data suggest that a microenvironment of proangiogenic cytokines and growth factors can trigger the establishment of a characteristic gene expression signature upon <i>CCM1</i> inactivation. Consequently, <i>CCM1</i>^−/− precursor cells may exist that remain silent until entering the endothelial lineage. Collectively, not only downstream consequences of <i>CCM1</i> ablation but also supporting factors must be addressed in CCM therapy development.