CRLF2 rearrangements in Ph-like ALL. (A) Interstitial deletion of the pseudoautosomal region (PAR1) of chromosomes X or Y places CRLF2 under control of the noncoding P2RY8 or CSF2RA promoters (dotted bar) to drive fusion transcript expression (thin arrows) and protein (thick arrows) translation (thin arrows). (B) IGH-CRLF2 fusion results from t(X;14) or t(Y;14). IGH is noncoding in the fusions (dotted bar). Both rearrangements result in CRLF2 overexpression and increased CRLF2 protein expression detectable by flow cytometry. (C) Rare CRLF2 point mutations lead to CRLF2 homodimerization and constitutive kinase signaling.