Cytokine receptor-like factor 2 (CRLF2) is a type I cytokine receptor subunit that dimerizes with IL7R to form the receptor for thymic stromal lymphopoietin (TSLP). Heterozygous, somatic, gain-of-function mutations introducing cysteines in the transmembrane domain have been described in up to 20% of B cell acute lymphoblastic leukemias (ALL). These mutations cause ligand independent dimerization via disulfide bonds. The disulfide bond is critical for the activation since elimination of the cysteines abrogated the cytokine independent growth. In addition, more recently, another activating, non-cysteine mutation in the heterodimerization domain of CRLF2 has been reported.