In ALL, CRLF2 alterations drive constitutive signaling and are linked to chemoresistance, though JAK inhibitors may offer targeted therapeutic options. High CRLF2 expression typically results from translocations involving CRLF2 and either P2RY8 or the immunoglobulin heavy chain (IGH) locus. The gene discussed is CRLF2; the disease is acute lymphoblastic leukemia.