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Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology., Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions., Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes., Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290-300. ©2015 AACR., (©2015 American Association for Cancer Research.)

Heterogeneous populations of saturable specific high-affinity binding sites for the biologically active subunit of the 7S nerve growth factor complex purified from mouse submaxillary gland (NGF) are detected on human tumor cells of neural crest origin. Detailed studies of the melanoma cell line MeWo demonstrate two populations of binding sites of high affinity with dissociation equilibrium constants of Kd 4 X 10(-11) and 5 X 10(-10) M, respectively. Other cell lines of neural crest origin also show high-affinity binding heterogeneity. Exposure of the cell lines to 1 mM theophylline reversibly reduces the number of available NGF binding sites without influencing the affinities of binding. On the MeWo cell line, this is not related to the stages of the cell cycle or to production and release of a NGF-like molecule by the theophylline-exposed cells. These observations complement earlier studies of theophylline-induced alterations in NK cell sensitivity on the MeWo cell line, providing further evidence for cell surface phenotypic changes induced by a compound that promotes differentiation in melanocytes and melanoma cells. Future studies of cell surface phenomena involved in theophylline-induced NGF binding site disappearance may lead to a better understanding of the NGF receptor and its disappearance from certain embryonic cells of neural crest origin during differentiation.