1: Leuk Lymphoma. 2003;44 Suppl 3:S21-6. 

Pathobiology of primary mediastinal B-cell lymphoma.

Pileri SA, Zinzani PL, Gaidano G, Falini B, Gaulard P, Zucca E, Sabattini E,
Ascani S, Rossi M, Cavalli F; International Extranodal Lymphoma Study Group.

Institute of Haematology Seragnoli, Bologna University, Policinico S. Orsola,
via Massarenti 9, 40138, Bologna, Italy. pileri@med.unibo.it

Controversy still exists over the response to therapy and prognosis of patients
with primary mediastinal B-cell lymphoma (PMBL). Recent data from the
International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B
(methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin)
chemotherapy regimen followed by radiotherapy may be a better induction strategy
than other previously used treatments. Although the pathobiology of PMBL has
been widely studied, its precise histology, phenotype, and molecular
characteristics are still not clear. To date, phenotypic analysis has revealed
the following phenotype: positivity for CD45 and CD20, but negativity for CD3,
CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other
immunohistochemical markers. CD79a is generally detected, despite an absence of
surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is
weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic
large cell lymphoma. BCL-2 protein is usually expressed but there are few data
describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell
transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains
in segments of chromosome 9p, including amplification of the REL proto-oncogene
and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc
mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2
and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are
generally absent, suggesting that PMBL is of pre-germinal center (GC) origin.
However, two recent reports show isotype-switched Ig genes with a high frequency
of somatic hypermutations as well as variants in the 5' noncoding region of the
bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review.
Histologically, the lymphomatous growth was predominantly diffuse with sclerosis
that induced compartmentalized cell aggregation. It consisted of large cells
with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm.
Molecular analysis was performed on 40 cases and showed novel findings. More
than half of the cases displayed bcl-6 gene mutations, which usually occurred
together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or
MUM1/IRF4 expression. The present study supports the concept that PBML is
derived from activated GC or post-germinal center cells. However, it differs
from other aggressive B-cell lymphomas in that it shows defective Ig production
despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a
lack of IgV(H) gene crippling mutations.

Publication Types:
    Review
    Review, Tutorial

PMID: 15202521 [PubMed - indexed for MEDLINE]


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2: J Immunol. 2004 Jan 15;172(2):1054-64. 

NF-kappa B and Oct-2 synergize to activate the human 3' Igh hs4 enhancer in B
cells.

Sepulveda MA, Emelyanov AV, Birshtein BK.

Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris
Park Avenue, Bronx, NY 10461, USA.

In B cells, the Igh gene locus contains several DNase I-hypersensitive (hs)
sites with enhancer activity. These include the 3' Igh enhancers, which are
located downstream of the Calpha gene(s) in both mouse and human. In vivo
experiments have implicated murine 3' enhancers, hs3B and/or hs4, in class
switching and somatic hypermutation. We previously reported that murine hs4 was
regulated by NF-kappaB, octamer binding proteins, and Pax5 (B cell-specific
activator protein). In this study we report that human hs4 is regulated
differently. EMSAs and Western analysis of normal B cells before and after
stimulation with anti-IgM plus anti-CD40 showed the same complex binding pattern
formed by NF-kappaB, Oct-1, and Oct-2 (but not by Pax5). A similar EMSA pattern
was detected in mature human B cell lines (BL-2, Ramos, and HS-Sultan) and in
diffuse large B cell lymphoma cell lines, although yin yang 1 protein (YY1)
binding was also observed. We have confirmed the in vivo association of these
transcription factors with hs4 in B cells by chromatin immunoprecipitation
assays. The diffuse large B cell lymphoma cell lines had a distinctive
slow-migrating complex containing YY1 associated with Rel-B. We have confirmed
by endogenous coimmunoprecipitation an association of YY1 with Rel-B, but not
with other NF-kappaB family members. Transient transfection assays showed robust
hs4 enhancer activity in the mature B cell lines, which was dependent on
synergistic interactions between NF-kappaB and octamer binding proteins. In
addition, human hs4 enhancer activity required Oct-2 and correlated with
expression of Oct coactivator from B cells (OCA-B).

PMID: 14707079 [PubMed - indexed for MEDLINE]


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