SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
some of these genes significantly correlates with
DLBCL survival. An expressed sequence tag (EST)
that the laboratory named human germinal
center-associated lymphoma (HGAL) (UniGene
cluster 49614 -Clone 814622,GI:2210537) was
identified as a best predictor of DLBCL survival.
The predictive power of HGAL was International
Prognostic Indicator (IPI) independent, as demonstrated
by multivariate analysis including components
of the IPI. Furthermore, the prognostic
power of HGAL expression in predicting survival
was also shown when its expression was considered
as a continuous variable demonstrating
direct correlation between higher levels of its
expression and longer survival. Higher HGAL
expression in ABC-like DLBCL still predicted
better overall survival. There was no difference in
the complete response rates between patients with
high and low HGAL expression, thus suggesting
that high HGAL expression was associated with
either better response to salvage treatment or
lower relapse rates due to more complete tumor
cell eradication or effective immunological
surveillance.
The laboratory has cloned the full-length
cDNA of this EST from both sorted GC lymphocytes
and from the Ramos cell line and
termed the gene human germinal center-associated
lymphoma (HGAL) (GenBank accession
number AF521911). HGAL is located on chromosome
3q13. Comparison of the genomic sequence
to the cDNA sequence revealed that
HGAL spans 11kb. Recognition of a Kozak sequence
and search for the longest open reading
frame (ORF) led to the identification of a putative
ORF extending from exon 1 to exon 6 and
encoding a 178 amino acid protein, with 51 percent
identity to the murine M17 protein that is
expressed in GC lymphocytes. The HGAL gene
product had a hydrophilic profile with no predicted
transmembrane domain and lacked a nuclear localization
sequence. HGAL contains a modified
immunoreceptor tyrosine-based activation motif
termed ITAM (D/EX 7
D/EX 2
YX 2
LX 7
YX 2
L) that
plays a role in signal transduction in B and T
lymphocytes. HGAL is not expressed in nonlymphoid
tissues but is expressed at high levels
only in GC lymphocytes, at intermediate levels in
memory B cells, and at relatively low levels in
peripheral blood B cells. In tumors, its expression
is high in follicular lymphoma tumors, low in
chronic lymphocytic leukemia cells, and heterogeneous
in DLBCL specimens. Thus, HGAL expression
may correlate with specific stages of
B-cell differentiation, especially the GC stage.
The function of HGAL in normal lymphocytes
and the reason its expression in DLBCL
correlates with better DLBCL outcome, are
not known. Whether the improved survival of
patients with high HGAL-content tumors is
attributed to specific function of this gene or
is a marker of important biologic characteristic
of the tumor is unknown. Researchers in Dr.
Lossos’ laboratory are currently investigating
these questions.
SELECTED PUBLICATIONS
2002
Lossos, IS , Or, R, Ginzburg, V, Christensen,
TG, Mashriki, Y, and Breuer, R. Cyclosporin
A upmodulates bleomycin-induced pulmonary
fibrosis in BALB/c mice. Respiration 69:344-49,
2002.
Auffermann-Gretzinger, S, Lossos, IS , Vayntrub,
TA, Leong, W, Grumet, FC, Blume, KG,
Stockerl-Goldstein, KE, Levy, R, and Shizuru,
JA. Rapid establishment of dendritic cell chimerism
in allogeneic hematopoietic cell transplant
recipients. Blood 99:1442-48, 2002.
Bokstein, F, Lossos, A, Lossos, IS, and Siegal, T.
Central nervous system relapse of systemic non-
Hodgkin’s lymphoma: results of treatment based
on high-dose methotrexate combination chemotherapy.
Leukemia & Lymphoma 43:587-93,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 49