Transcriptional reprogramming by mutated IRF4 in lymphoma.

Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma.

Temporal autoregulation during human PU.1 locus SubTAD formation.

Epigenetic control of gene expression occurs within discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in cancer. We therefore applied high-resolution chromosomal conformation capture sequencing to map the three-dimensional (3D) organization of the human locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells.

Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors.

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells.

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.

The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant.

Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALK gene (ALK(+) and ALK(-) ALCL). The interferon regulatory factor 4 (IRF4) is known to be highly expressed in both ALK(+) and ALK(-) ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear.

Gene expression profiling of peripheral blood mononuclear cells during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer: tumor-induced immunosuppression and a possible role for NF-κB.

Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified [interleukin-7 (IL-7)/CD80-cotransfected] renal cell cancer (RCC) vaccine failed to induce clinically relevant TH-1-polarized immune responses, peripheral blood mononuclear cells from enrolled study patients were analyzed by gene expression profiling (GEP) both prior and after vaccination. At baseline before vaccination, a profound downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines and signaling/transcription factors was observed in RCC patients as compared to healthy controls.