Adnan Mansoor

Cellular pathways for induction of programmed cell death (PCD) have been identified, but little is known about specific extracellular matrix processes that may affect apoptosis along those pathways. In this study, a series of Burkitt's lymphoma (BL) cell lines were assayed for their expression of tissue inhibitor of metalloproteinases (TIMP)-1. Results indicate that TIMP-1-positive BL lines show resistance to cold-shock-induced apoptosis. Furthermore, recombinant TIMP-1, but not TIMP-2 or a synthetic metalloproteinase inhibitor (BB-94), confers resistance to apoptosis induced by both CD95-dependent and -independent (cold shock, serum deprivation, and gamma-radiation) pathways in TIMP-1-negative BL lines. TIMP-1 suppression of PCD is not due to metalloproteinase inhibition, as reduction and alkylation of the TIMP-1 did not abolish this activity. Retroviral induction of TIMP-1 not only resulted in cell survival but also in continued DNA synthesis for up to 5 d in the absence of serum, while controls underwent apoptosis. This resistance to apoptosis is reversed by anti-TIMP-1 antibodies, demonstrating that secreted TIMP-1 is active in blocking apoptosis. Furthermore, TIMP-1 upregulation induced expression of Bcl-XL but not Bcl-2 as well as decreased NF-kappaB activity as compared with controls. These results demonstrate that TIMP-1 suppresses apoptosis in B cells and suggests a novel activity for TIMP-1 in tissue homeostasis.

Although the combination of lenalidomide and dexamethasone is effective therapy for patients with relapsed/refractory multiple myeloma, the influence of high-risk cytogenetic abnormalities on outcomes is unknown. This subanalysis of a large, open-label study investigated the effects of the most common unfavorable cytogenetic abnormalities detected by fluorescence in situ hybridization, del(13q), t(4;14), and del(17p13), in 130 evaluable patients treated with this regimen. Whereas patients with either del(13q) or t(4;14) experienced a median time to progression and overall survival comparable with those without these cytogenetic abnormalities, patients with del(17p13) had a significantly worse outcome, with a median time to progression of 2.22 months (hazard ratio, 2.82; P < .001) and median overall survival of 4.67 months (hazard ratio, 3.23; P < .001). Improved therapeutic strategies are required for this subgroup of patients. This study was registered at www.ClinicalTrials.gov as #NCT00179647.

Intestinal T-cell and natural killer (NK)-cell lymphomas are clinically aggressive and can be challenging to diagnose in small endoscopic biopsies. We describe 8 patients in whom atypical NK-cell lymphoproliferative lesions mimicked NK- or T-cell lymphoma. The patients (2 men; 6 women; ages 27-68 years) presented with vague gastrointestinal symptoms with lesions involving stomach, duodenum, small intestine, and colon. At endoscopy, the lesions exhibited superficial ulceration, edema, and hemorrhage. Biopsies revealed a mucosal infiltrate of atypical cells with an NK-cell phenotype (CD56(+)/TIA-1(+)/Granzyme B(+)/cCD3(+)), which displaced but did not invade the glandular epithelium. Epstein-Barr virus-encoded RNA in situ hybridization was negative, and T-cell receptor-γ gene rearrangement showed no evidence of a clonal process. Based on an original diagnosis of lymphoma, 3 patients received aggressive chemotherapy followed by autologous bone marrow transplantation in 2. Five patients were followed without treatment. However, no patient developed progressive disease or died of lymphoma (median follow-up, 30 months). Repeat endoscopies in 6 of 8 patients showed persistence or recurrence of superficial gastrointestinal lesions. This unique entity mimics intestinal and NK-/T-cell lymphomas on endoscopic biopsies and can result in erroneous diagnosis, leading to aggressive chemotherapy. We propose the term "NK-cell enteropathy" for this syndrome of as yet unknown etiology.

Integrin-β7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-β7 in MM are largely unknown. Clinically, we have correlated integrin-β7 expression in MM with poor survival outcomes post autologous stem cell transplantation and postsalvage therapy with bortezomib. Functionally, we have found that shRNA-mediated silencing of ITGB7 reduces MM-cell adhesion to extra-cellular matrix elements (fibronectin, E-cadherin) and reverses cell-adhesion-mediated drug resistance (CAM-DR) sensitizing them to bortezomib and melphalan. In addition, ITGB7 silencing abrogated MM-cell transwell migration in response to SDF1α gradients, reduced vessel density in xenografted tumors, and altered MM cells in vivo homing into the BM. Mechanistically, ITGB7 knockdown inhibited focal adhesion kinase (FAK) and Src phosphorylation, Rac1 activation, and SUMOylation, reduced VEGF production in MM-BM stem cell cocultures and attenuated p65-NF-κB activity. Our findings support a role for integrin-β7 in MM-cell adhesion, migration, and BM homing, and pave the way for a novel therapeutic approach targeting this molecule.