CRLF2 (cytokine receptor-like factor 2) functions as a receptor for thymic stromal lymphopoietin (TSLP), forming a functional complex with TSLP and IL7R to stimulate cell proliferation through STAT3 and STAT5 activation 1. The receptor also activates JAK2 signaling and plays a role in hematopoietic system development. Clinically, CRLF2 alterations are highly significant in acute lymphoblastic leukemia (ALL). CRLF2 rearrangements represent a major subclass of Philadelphia chrX|Y-like (Ph-like) ALL, activating JAK/STAT signaling and conferring kinase-dependent proliferation 2. CRLF2-rearranged ALL occurs across pediatric and adult populations and is recognized as a distinct molecular subtype in current ALL classification systems 3. Notably, CRLF2 rearrangements are substantially enriched in Down syndrome-associated ALL, representing a major molecular subtype, with BCR::ABL1-like CRLF2-rearranged cases associated with inferior event-free survival 4. CRLF2/JAK pathway mutations in Ph-like ALL are potentially amenable to JAK-directed tyrosine kinase inhibitor therapy, with clinical trials investigating targeted approaches for this high-risk ALL subset 5. Additionally, CRLF2 is expressed on specific immune cell populations (TH2A cells) in atopic dermatitis, where it functions as a receptor for TSLP and contributes to Th2-skewed immune responses 6.