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Germline RUNX1 variants have been identified in relation to myeloid malignancy predisposition, with lymphoid hematological malignancies present at a lower frequency in families. In this issue of the JCI, Li and Yang et al. examined the frequency and type of germline RUNX1 variants in pediatric patients with acute lymphoblastic leukemia (ALL). Patients with T cell ALL (T-ALL) harbored rare, damaging RUNX1 mutations that were not seen in patients with B cell ALL (B-ALL). Further, several of the T-ALL-associated RUNX1 variants had potential dominant-negative activity. RUNX1-mutated T-ALL cases were also associated with somatic JAK3 mutations and enriched for the early T cell precursor (ETP) leukemia subtype, a finding that was validated when RUNX1 and JAK3 mutations were combined in mice. This study confirms germline RUNX1 predisposition beyond myeloid malignancy, demonstrates the importance of examining both germline and somatic mutations in malignancy cohorts, and demarcates the ETP ALL subtype as a flag for germline predisposition in patients.

To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition