The CRLF2 protein interacts with IL7R to form a receptor for TSLP, binding of which activates cell signaling through JAK/STAT pathways. Approximately 7% of patients with B-cell precursor ALL (B-ALL) and more than 50% of B-ALL in children with Down syndrome harbor alterations involving the CRLF2 gene. These include the translocations t(X;14)(p22.33;q32.3) or t(Y;14) (p11.32;q32.3) which fuse the entire CRLF2 gene to the immunoglobulin heavy chain enhancer region (IGH-CRLF2). Another common alteration is an interstitial deletion involving the pseudoautosomal region (PAR1) of the sex chromosomes upstream of CRLF2, juxtaposing the first non-coding exon of P2RY8 to the entire coding region of CRLF2 (P2RY8-CRLF2). These rearrangements, which are often accompanied by JAK mutations, result in overexpression of CRLF2 and were shown to contribute to lymphoid transformation. Patients with CRLF2 rearrangements and JAK mutations have a poor event-free and overall survival. Moreover, the detection of CRLF2 rearrangements by FISH may help in selecting B-ALL patients eligible for therapy with inhibitors of the JAK/STAT pathway.