Molecular Pathogenesis of Aids-Related Lymphomas

Gaïdano, Gianluca; Dalla‐Favera, Riccardo

doi:10.1016/s0065-230x(08)60712-5

Cited by 69 publications

(43 citation statements)

References 229 publications

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“…HIV-1 creates a milieu of combined immune suppression and chronic antigenic stimulation in lymph nodes. 40 This environment with dysregulated cytokine/chemokine release and B-cell hyperstimulation 41 along with the presence of concomitant infection (eg, Epstein-Barr virus, human herpesvirus type 8, cytomegalovirus) may promote a permissive environment for HIV-1-induced B-cell expansion and impaired immune surveillance, culminating in lympho-proliferative disorders. 42 Up until now, the molecular mechanisms responsible for B-cell transformation associated with ARLs have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Caccuri

Rueckert

Giagulli

et al. 2014

ATVB

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Objective— AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. Approach and Results— Human primary lymph node–derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node–derived lymphatic endothelial cells and activating the Akt/extracellular signal–regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node–derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. Conclusions— Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Caccuri

Rueckert

Giagulli

et al. 2014

ATVB

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“…Also that immunosuppressed people should be treated like immunocompetent patients assume adequate support and infectious prophylaxis in the former. One possible explanation for the favourable impact on response and survival to cART is that control of viral replication might decrease the continuous activation of the lymphoid system, which is one of the features involved in AIDS-related lymphomagenesis [110].…”

Section: The Cart Eramentioning

confidence: 99%

Human immunodeficiency and Hodgkin lymphoma

Sissolak

Jacobs

2010

Transfusion and Apheresis Science

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Presentation of Hodgkin lymphoma (HL) is distinctive in the infected individual being more advanced, accompanied by B symptoms and the presence of extranodal disease particularly lymphadenopathy of the head and neck. Bone marrow involvement may be found in over 50% of cases. Virtually all co express gamma-herpesvirus. Phenotypically there is prominence of the mixed-cellularity and lymphocyte depleted histopathologic subtypes that define an aggressive clinical course in comparison to other variants. Prior to the induction of cART, median survival was only 1-2 years. Notably the first chemotherapy trial using ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in 21 patients, without treating the viral infection, resulted in a 43% complete remission rate accompanied by severe haematological toxicities but did not extend median survival with this being 1.5 years matching the negative cases.Significant change accompanied concomitant anti-retroviral therapy that could be given safely even with dose intensive regimens exemplified by BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in 12 patients or the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone) coupled with involved-field radiation for bulky disease studied in 59 patients. BEACOPP extended overall survival (OS) to 83% at 2 years. A similar trend was seen 1 when using the Stanford V regimen with an OS rate of 51% at 3 years, disease-free survival (DFS) of 68% and freedom from progression (FFP) in 60%. Additional benefits accrued from supportive care with stimulatory peptides such as G-CSF and when combined with bacterial prophylaxis results approached that found in the uninfected reference group. Current consensus holds this particular lymphoma as still among the non-AIDS defining cancers being lung, stomach, liver or anal despite these having recently gained more attention as several of these neoplasms may be occurring more commonly in the era of cART.While the relative risk of developing a non-AIDS-defining neoplasm in HIV-infected persons on the average is 2-3 times, the risk for developing HL in HIV-infected cases impressively ranges between 5 and 25 times when compared to the general population. Based on the precedent in which Kaposi sarcoma and the non-Hodgkin lymphomas distinctively alter the course of this retroviral infection in a way indistinguishable from concurrent Hodgkin lymphoma we propose that this entity be similarly regarded and the hypothesis tested in large randomised prospective study.

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“…10 Many previous studies have shown that genetic lesion on both c-MYC and p53 genes co-exist in some lymphoid malignancies such as Burkitt's lymphoma and AIDS-associated Burkitt's lymphoma. 11,12 These disorders share a common pathogenetic pathway represented by c-MYC activation due to chromosomal translocation in almost 100% of the cases and p53 disruption in 40-60%. Furthermore, using transgenic mice, Blyth and colleagues 13 showed that overexpressed c-MYC and loss of p53 function act synergistically to promote lymphoid tumors, suggesting that those tissues with an abnormally expressed c-MYC protein may gain an additional growth advantage by mutating the p53 gene.…”

Section: Discussionmentioning

confidence: 99%

True

1999

Leukemia

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We report the cytogenetic, molecular and biological characterization of a case of B-PLL with a complex karyotype and concurrent abnormalities on the p53 and c-MYC genes. Conventional cytogenetics suggested that both 17q arms were translocated to chromosomes 1q and 14p, respectively, whereas both 17p arms were not identified. In addition, a Burkitt's-like variant translocation t(2;8) was found. Study of loss of heterozygosity at 17p13 and p53 direct sequencing demonstrated the presence of only one copy of the p53 gene. A 27 bp deletion in exon 8 that resulted in the expression of a p53 protein lacking nine amino acids from the DNA binding region was also found. To confirm the presence of one copy of the p53 gene and localize it, fluorescent in situ hybridization (FISH) studies using a p53 gene probe was performed. Only one signal of p53 was visualized. Moreover, the DAPI profile of the chromosome containing the hybridization spot for the p53 probe did correspond to the cytogenetic marker identified as der (14) B cell prolymphocytic leukemia (B-PLL) is a distinct and aggressive form of B cell leukemia characterized by a high white cell count and splenomegaly without significant lymphadenopathy. Cytogenetic studies have shown that B-PLL usually presents a complex cytogenetic karyotype 1 with a 14q+ as the most frequent abnormality. Abnormalities on chromosome 17 have also been described. Recently, we reported a high incidence of p53 mutations in B-PLL. 2 In addition, the t(8;14)(q24;q32) translocation -classical of Burkitt's lymphoma -has been reported in 3/23 (13%) of cases. 3 We describe here the cytogenetic, molecular and biological characterization of a case of B-PLL with a complex karyotype and concurrent abnormalities on the p53 and c-MYC genes. Case presentationA 73-year-old woman presented in March 1991 with left hypochondrial pain and weakness. On examination, the spleen was enlarged 16 cm below the costal margin, but neither lymphadenopathy nor hepatomegaly were found. Blood counts showed hemoglobin 13 g/dl, platelets 150 ×

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Molecular Pathogenesis of Aids-Related Lymphomas

Cited by 69 publications

References 229 publications

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Human immunodeficiency and Hodgkin lymphoma

True

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