Approximately 50% of Ph-like ALL manifest CRLF2 lesions, with overexpression being a hallmark driven by different mechanisms, including 1) P2RY8::CRLF2 fusion (due to a cryptic deletion within the pseudoautosomal region 1 (PAR1) of the sex chromosomes, which juxtaposes CRLF2 to the P2RY8 promoter; 2) CRLF2 translocation at IGH locus, positioning CRLF2 under the control of the immunoglobulin promoter; 3) CRLF2 single-nucleotide variants (SNVs; with p.F232C as the most frequent); and 4) other JAK-STAT pathway activating variants (i.e., JAK2 p.R683G) (Roberts et al., 2018). The gene discussed is CRLF2; the disease is acute lymphoblastic leukemia.