Figure 1 demonstrates the CRLF2 receptor complex and downstream pathways. Rearrangement of the CRLF2 gene located on Xp22.3 and Yp11.3, with the resulting overexpression of the CRLF2 receptor complex is seen in 10–15% [28,30] of all high-risk B-ALL. Among Ph-like B-ALL, the prevalence of CRLF2 rearrangement can be as low as 24% in children with NCI-standard risk disease to as high as 60% in adolescents [9,14]. It was first described by Russell et al. in 2009 [59] in a UK cohort of B-ALL and subsequently by Harvey et al. in a US cohort [30]. Here, CRLF2 is linked to precursor B-cell acute lymphoblastic leukemia.