Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk.

The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Nevertheless, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Numerous studies have indicated that bystander cells provide chronic lymphocytic leukemia-supportive functions, but it has also become clear that chronic lymphocytic leukemia cells actively engage in the formation of a supportive tumor microenvironment through several cross-talk mechanisms. In this review, we describe how chronic lymphocytic leukemia cells participate in this interplay by inducing migration and tumor-supportive differentiation of bystander cells. Furthermore, chronic lymphocytic leukemia-mediated alterations in the interactions between bystander cells are discussed. Upon bystander cell interaction, chronic lymphocytic leukemia cells secrete cytokines and chemokines such as migratory factors [chemokine (C-C motif) ligand 22 and chemokine (CC motif) ligand 2], which result in further recruitment of T cells but also of monocyte-derived cells. Within the tumor microenvironment, chronic lymphocytic leukemia cells induce differentiation towards a tumor-supportive M2 phenotype of monocyte-derived cells and suppress phagocytosis, but also induce increased numbers of supportive regulatory T cells. Like other tumor types, the differentiation of stromal cells towards supportive cancer-associated fibroblasts is critically dependent on chronic lymphocytic leukemia-derived factors such as exosomes and platelet-derived growth factor. Lastly, both chronic lymphocytic leukemia and bystander cells induce a tolerogenic tumor microenvironment; chronic lymphocytic leukemia-secreted cytokines, such as interleukin-10, suppress cytotoxic T-cell functions, while chronic lymphocytic leukemia-associated monocyte-derived cells contribute to suppression of T-cell function by producing the immune checkpoint factor, programmed cell death-ligand 1. Deeper understanding of the active involvement and cross-talk of chronic lymphocytic leukemia cells in shaping the tumor microenvironment may offer novel clues for designing therapeutic strategies.

Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling.

Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR-affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro-survival protein Mcl-1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl-1 antagonist Noxa, more low-affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen-specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF-R signaling towards Mcl-1.