CRLF2

CRLF2, or cytokine receptor-like factor 2, is a gene that encodes a single-pass transmembrane protein resembling a cytokine receptor. It forms part of the receptor for thymic stromal lymphopoietin (TSLP) by pairing with the interleukin-7 receptor alpha chain (IL7Rα). The CRLF2/IL7Rα receptor complex binds TSLP and activates intracellular signaling cascades, including JAK-STAT, PI3K-AKT, and MAPK pathways, promoting survival and proliferation of early lymphoid cells.

CRLF2 expression is highest in hematopoietic tissues and it participates in normal lymphoid development and immune responses. The gene plays a role in signaling events that influence B and T cell precursors during development.

Genetic alterations involving CRLF2 are clinically significant in certain leukemias. In B-cell acute lymphoblastic leukemia (B-ALL), rearrangements or copy-number alterations can lead to overexpression of CRLF2. The most common rearrangement is the P2RY8-CRLF2 fusion, created by an intrachromosomal deletion that places CRLF2 under the control of the P2RY8 promoter. Other CRLF2 rearrangements or amplifications also occur. These alterations are particularly frequent in Down syndrome-associated ALL and, in some cohorts, are associated with poorer prognosis or increased relapse risk, especially when accompanied by activating mutations in the JAK-STAT pathway.

Clinical impact and testing: CRLF2 alterations are detected by fluorescence in situ hybridization (FISH), RT-PCR, or RNA sequencing. The finding can influence risk stratification and may guide consideration of targeted therapies. JAK inhibitors, such as ruxolitinib, have been explored in CRLF2-rearranged ALL and related contexts, but their use remains under investigation.