As ETV6::RUNX1 and P2RY8::CRLF2 each define distinct molecular subclasses of B-ALL with unique mutational landscapes and prognoses, the authors highlighted that co-existing leukemogenic aberrations may significantly modify treatment response and relapse risk but are often missed in initial workups relying solely on standard cytogenetics. Here, CRLF2 is linked to precursor B-cell acute lymphoblastic leukemia.