Grant Number:	2R01CA073475-05A2 Interpret this number
Primary Investigator:	Martinez-Maza, Otoniel
Organization:	Children'S Hospital-La
Project Title:	Molecular Epidemiology of AIDS-Associated Lymphoma
Fiscal Year:	2002

DESCRIPTION (Provided by the applicant): Non-Hodgkin' s B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in HIV-infected people, not only in North America and Europe, but worldwide. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-lymphoma. The proposed studies will utilize the resources of the Multicenter AIDS Cohort Study of the Natural History of AIDS (MACS). In prior studies supported by this award, elevated levels of various immune system molecules that are associated with B cell activation, including IL6 and IL10, sCD23, sCD27, sCD44, and IgE, were seen prior to the clinical detection of AIDS-lymphoma. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-lymphoma (Burkitt's/SNCCL vs. other subtypes), suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, in very recent work we saw that a single-nucleotide polymorphism (SNP) in the IL10 promoter (-592 C/C), which is known to result in increased expression of IL10, was associated with the development of AIDS-lymphoma. These findings are of great significance, since few risk factors have been identified for AIDS-lymphoma. The specific aims of the proposed studies are to determine: I ) if enhanced B cell stimulation, elevated immunoglobulin isotype switch activity, detectable c-myc:Ig gene translocations, and/or detectable circulating B cells with a germinal center-like phenotype, precede the development of AIDS- lymphoma, 2) if SNPs in the genes encoding B cell-stimulatory cytokines (IL6, IL10, TNFalpha, LTalpha, RANTES) are associated with an elevated risk for the development of AIDS-lymphoma, and 3) if subjects who have a genotype that has been seen to be associated with a decreased risk for developing AIDS-lymphoma (CCR5 delta-32 heterozygotes, SDF-1 3'UTR 801 G/G SNP, or IL10 promoter -592 A/A or A/C SNP) show lower levels of B cell activation. The accomplishment of these specific aims will add valuable new information to our understanding of the molecular epidemiology of AIDS-lymphoma, as well as the role of immune dysfunction in the generation and growth of this cancer. This information could form the foundation for future studies on the pathogenesis of AIDS-lymphoma, and may lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier and more effective clinical intervention.




B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma.
Authors: Breen E.C. , Hussain S.K. , Magpantay L. , Jacobson L.P. , Detels R. , Rabkin C.S. , Kaslow R.A. , Variakojis D. , Bream J.H. , Rinaldo C.R. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2011 Jul; 20(7), p. 1303-14.
PMID: 21527584
Related Citations

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation.
Authors: Regidor D.L. , Detels R. , Breen E.C. , Widney D.P. , Jacobson L.P. , Palella F. , Rinaldo C.R. , Bream J.H. , Martínez-Maza O. .
Source: Aids (london, England), 2011-01-28 00:00:00.0; 25(3), p. 303-14.
PMID: 21192231
Related Citations

HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma.
Authors: Epeldegui M. , Vendrame E. , Martínez-Maza O. .
Source: Immunologic Research, 2010 Dec; 48(1-3), p. 72-83.
PMID: 20717742
Related Citations

Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study.
Authors: Wong H.L. , Breen E.C. , Pfeiffer R.M. , Aissani B. , Martinson J.J. , Margolick J.B. , Kaslow R.A. , Jacobson L.P. , Ambinder R.F. , Chanock S. , et al. .
Source: Aids (london, England), 2010-04-24 00:00:00.0; 24(7), p. 1025-33.
PMID: 20299965
Related Citations

Expression and Function of the Chemokine, CXCL13, and Its Receptor, CXCR5, in Aids-Associated Non-Hodgkin's Lymphoma.
Authors: Widney D.P. , Gui D. , Popoviciu L.M. , Said J.W. , Breen E.C. , Huang X. , Kitchen C.M. , Alcantar J.M. , Smith J.B. , Detels R. , et al. .
Source: Aids Research And Treatment, 2010; 2010, p. 164586.
PMID: 21490903
Related Citations

The major histocompatibility complex conserved extended haplotype 8.1 in AIDS-related non-Hodgkin lymphoma.
Authors: Aissani B. , Ogwaro K.M. , Shrestha S. , Tang J. , Breen E.C. , Wong H.L. , Jacobson L.P. , Rabkin C.S. , Ambinder R.F. , Martinez-Maza O. , et al. .
Source: Journal Of Acquired Immune Deficiency Syndromes (1999), 2009-10-01 00:00:00.0; 52(2), p. 170-9.
PMID: 19654554
Related Citations

Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis.
Authors: Epeldegui M. , Breen E.C. , Hung Y.P. , Boscardin W.J. , Detels R. , Martínez-Maza O. .
Source: Aids (london, England), 2007-11-12 00:00:00.0; 21(17), p. 2265-70.
PMID: 18090274
Related Citations

The effect of atopy, childhood crowding, and other immune-related factors on non-Hodgkin lymphoma risk.
Authors: Cozen W. , Cerhan J.R. , Martinez-Maza O. , Ward M.H. , Linet M. , Colt J.S. , Davis S. , Severson R.K. , Hartge P. , Bernstein L. .
Source: Cancer Causes & Control : Ccc, 2007 Oct; 18(8), p. 821-31.
PMID: 17588155
Related Citations

Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations.
Authors: Epeldegui M. , Hung Y.P. , McQuay A. , Ambinder R.F. , Martínez-Maza O. .
Source: Molecular Immunology, 2007 Feb; 44(5), p. 934-42.
PMID: 16730063
Related Citations

Pathogenesis of AIDS lymphoma: role of oncogenic viruses and B cell activation-associated molecular lesions.
Authors: Epeldegui M. , Widney D.P. , Martínez-Maza O. .
Source: Current Opinion In Oncology, 2006 Sep; 18(5), p. 444-8.
PMID: 16894291
Related Citations

Elevated serum soluble CD30 precedes the development of AIDS-associated non-Hodgkin's B cell lymphoma.
Authors: Breen E.C. , Fatahi S. , Epeldegui M. , Boscardin W.J. , Detels R. , Martínez-Maza O. .
Source: Tumour Biology : The Journal Of The International Society For Oncodevelopmental Biology And Medicine, 2006; 27(4), p. 187-94.
PMID: 16651853
Related Citations

Serum levels of the homeostatic B cell chemokine, CXCL13, are elevated during HIV infection.
Authors: Widney D.P. , Breen E.C. , Boscardin W.J. , Kitchen S.G. , Alcantar J.M. , Smith J.B. , Zack J.A. , Detels R. , Martínez-Maza O. .
Source: Journal Of Interferon & Cytokine Research : The Official Journal Of The International Society For Interferon And Cytokine Research, 2005 Nov; 25(11), p. 702-6.
PMID: 16318584
Related Citations

Elevated levels of soluble CD44 precede the development of AIDS-associated non-Hodgkin's B-cell lymphoma.
Authors: Breen E.C. , Epeldegui M. , Boscardin W.J. , Widney D.P. , Detels R. , Martínez-Maza O. .
Source: Aids (london, England), 2005-10-14 00:00:00.0; 19(15), p. 1711-2.
PMID: 16184051
Related Citations

Expression and function of CD28 on Epstein-Barr virus-positive B cell lines and AIDS-associated non-Hodgkin's lymphoma cell lines.
Authors: Widney D. , Boscardin W.J. , Kasravi A. , Martínez-Maza O. .
Source: Tumour Biology : The Journal Of The International Society For Oncodevelopmental Biology And Medicine, 2003 Mar-Apr; 24(2), p. 82-93.
PMID: 12853703
Related Citations

B-cell activation and lymphoma in patients with HIV.
Authors: Martínez-Maza O. , Breen E.C. .
Source: Current Opinion In Oncology, 2002 Sep; 14(5), p. 528-32.
PMID: 12192272
Related Citations

Viral interleukin 6 stimulates human peripheral blood B cells that are unresponsive to human interleukin 6.
Authors: Breen E.C. , Gage J.R. , Guo B. , Magpantay L. , Narazaki M. , Kishimoto T. , Miles S. , Martínez-Maza O. .
Source: Cellular Immunology, 2001-09-15 00:00:00.0; 212(2), p. 118-25.
PMID: 11748928
Related Citations

Aberrant expression of CD27 and soluble CD27 (sCD27) in HIV infection and in AIDS-associated lymphoma.
Authors: Widney D. , Gundapp G. , Said J.W. , van der Meijden M. , Bonavida B. , Demidem A. , Trevisan C. , Taylor J. , Detels R. , Martínez-Maza O. .
Source: Clinical Immunology (orlando, Fla.), 1999 Nov; 93(2), p. 114-23.
PMID: 10527687
Related Citations

Human herpesvirus 8-encoded interleukin 6 activates HIV-1 in the U1 monocytic cell line.
Authors: Gage J.R. , Breen E.C. , Echeverri A. , Magpantay L. , Kishimoto T. , Miles S. , Martínez-Maza O. .
Source: Aids (london, England), 1999-10-01 00:00:00.0; 13(14), p. 1851-5.
PMID: 10513642
Related Citations

The development of AIDS-associated Burkitt's/small noncleaved cell lymphoma is preceded by elevated serum levels of interleukin 6.
Authors: Breen E.C. , van der Meijden M. , Cumberland W. , Kishimoto T. , Detels R. , Martínez-Maza O. .
Source: Clinical Immunology (orlando, Fla.), 1999 Sep; 92(3), p. 293-9.
PMID: 10479534
Related Citations

Immune dysfunction and the pathogenesis of AIDS-associated non-Hodgkin's lymphoma.
Authors: Martínez-Maza O. , Widney D. , van der Meijden M. , Knox R. , Echeverri A. , Breen E.C. , Magpantay L. , Miles S.A. .
Source: Memo¿rias Do Instituto Oswaldo Cruz, 1998 May-Jun; 93(3), p. 373-81.
PMID: 9698872
Related Citations