ALK R1275Q mutation drives expansion of SCP-like cells during sympathoadrenal commitment and primes neuroblastoma initiation.
Neuroblastoma (NB) is a pediatric malignancy developing in the sympathoadrenal lineage of the neural crest, characterized by clinical heterogeneity ranging from spontaneous regression to poor outcomes. Activating mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) are frequently observed in both sporadic and familial NB, yet the functional role of ALK in tumor initiation is not fully understood. Using a patient-derived human induced pluripotent stem cell (iPSC) model of sympathoadrenal development, we show that upon sympathoadrenal lineage commitment, ALK R1275Q, the most common hotspot mutation found in familial NB, sustain a proliferative, immature Schwann cell precursor (SCP)-like cell state with elevated ALK signaling and increased susceptibility to MYCN-driven transformation. While ALK-mutant cells alone did not form tumors in vivo, they cooperated with MYCN to accelerate tumor initiation, suggesting that ALK R1275Q creates a permissive but insufficient state for transformation. These findings define an ALK-driven cell progenitor-like state that facilitates the initiation of NB during embryonal development.