CCR4 mutations act as key factors in adult T-cell leukemia/lymphoma pathogenesis


Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell lymphoma mostly occurred in the blood, lymph nodes and skin. This malignancy induced by T-cell lymphotropic virus type-I (HTLV-I) remains hard to predict and cure. Nakagawa et al. reported the dysregulation of CC chemokine receptor 4 (CCR4) is critical in ATLL pathogenesis, and the inhibition of CCR4 signaling may have clinical value for curative treatment of ATLL. The article was published in The Journal of Experimental Medicine.


By knowing CCR4 is expressed at high level in ATLL patients, researchers preformed whole transcriptome sequencing and found gain-of-function mutations in CCR4. One of the mutation isoforms, CCR4-Q330, was proved to promote the migration of ATLL cells toward the CCR4 ligands CCL17 and CCL22. The improved chemotaxis in part caused by the impairment of mutant CCR4 receptor internalization after binding to ligands. Furthermore, two possible reasons of ATLL pathogenesis depends on CCR4 mutations were proved: 1) the improved migration of ATLL cells toward favorable environment with high concentration of chemokine may support cancer cell proliferation and survival; 2) the binding of mutant CCR4 to ligands may activate downstream signaling pathways, including PI3K/AKT pathway, which is a key regulator of cell proliferation and longevity. These findings indicate the key role of CCR4 mutation in ATLL pathogenesis, and provide a rationale for the development of ATLL therapeutic strategy that inhibits CCR4 signaling.


J Exp Med. 2014 Dec 15;211(13):2497-2505.

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