In the setting of BCR-ABL1-like B-ALL, JAK mutations are associated with concomitant IKZF1 (Ikaros) and CDKN2A/B (p16) alterations. JAK2 mutations are also associated with CRLF2 rearrangements, and have been described in 60% of Down syndrome-associated ALL. Here, CRLF2 is linked to acute lymphoblastic leukemia.