LAUSR

In chronic lymphocytic leukemia (CLL), homing and retention of leukemic cells inside tissue niches represent crucial steps of disease progression. CLL trafficking from bloodstream into microenvironments is actively coordinated by transient interactions with endothelium through adhesion molecules and chemokines that trigger integrin activation, inducing firm adhesion and transendothelial migration into tissues. This process allows leukemic cells to invade the microenvironmental niches and generate a favorable soil for their survival, proliferation, and clonal evolution. CD49d, the α-chain of α4β1 (VLA-4) integrin heterodimer, has a pivotal role in CLL migration and retention into lymph nodes and bone marrow. VLA-4 mediates CLL interaction with accessory cells and tissue matrix by binding to its ligands vascular cell adhesion molecule-1 (VCAM-1) and fibronectin [1]. CD49d is a strong negative prognosticator in CLL, expressed at high levels in about 40% of CLL patients showing aggressive clinical course and shorter overall survival [2]. Increased levels of CD49d were reported to identify those patients under ibrutinib treatment with reduced lymphocytosis, inferior nodal response, and shorter progression-free survival [3]. Of interest, CD49d is almost universally expressed in CLL cases harboring trisomy 12 aberration (Tri12 CLL). Among the wide clinico-biological heterogeneity of CLL patients, Tri12 CLL represents a distinctive subset (about 15% of cases) characterized by the prevalence of nodal presentation, pronounced lymphadenopathy, and by higher rates of cell proliferation, disease progression, and Richter syndrome transformation [4, 5]. Tri12 CLL cells have an increased ability to migrate towards lymph nodes and reside inside tissue niches [6]. These patients show a significant abbreviated redistribution of B lymphocytes during ibrutinib treatment probably due to increased integrin-mediated signaling [7]. The reason why CLL patients harboring trisomy 12 abnormality are characterized by a more pronounced expression of CD49d and tropism toward lymph node is still under investigation. IRF4 is a member of the IRF family of transcription factors that exerts critical functions in different cell types of the immune system. In mature B cells, different IRF4 concentrations underlie the generation of alternative fate in cells localized in secondary lymphoid organs, promoting at lower levels the formation of germinal center reaction and class switch recombination or, conversely inducing, at higher concentrations, terminal plasma cell differentiation [8]. In CLL setting, a causal relationship between low levels of IRF4 and the development of CLL was demonstrated in two different mouse models, suggesting a possible pathogenic role of IRF4 in CLL [9, 10]. B cells deficient of IRF4 show an enrichment of genes involved in cell migration and homing, in particular of VLA-4 [11]. Here, we wondered whether IRF4 may regulate CD49d expression in CLL. We first evaluated IRF4 levels in a cohort of untreated CLL patients (n= 223, Fig. 1a). IRF4 expression was significantly reduced in CD49d-positive CLL (cut-off 30%) as compared to CD49d-negative CLL subset (P < 0.0001). In line with this observation, Tri12 These authors contributed equally: Roberto Marasca, Rossana Maffei