Haematologica 2003 - Supplements

clear that the biggest challenge for the future will be to integrate
this information, derived from the multiple techniques, multiple
cohorts of patients and different stages of the disease. We need
to integrate it all in a coherent model of disease pathogenesis.
While this seems an ambitious task, the high power of high
throughput technology coupled with the careful and detailed
classical molecular studies should help elucidate some of these
complex interactions. Furthermore confirmatory experimental
studies are needed to validate observations emanating form the
ongoing genetic studies of MM. For instance the presence of
silencing of tumor suppressor genes (e.g. p16 methylation) will
need to be evaluated in the context of its downstream signaling
pathways, its relation to the baseline genetic abnormalities
deregulating the CDK/CyclinD1 pathway, its impact on clinical
outcome and its relationship to therapy responsiveness.
9. CONCLUSION: A genetic and molecular cytogenetic
classification of MM is being formed by the work of multiple
laboratories that soon will likely integrate a global model for the
pathogenesis of the disease. Genetic abnormalities correlate
closely with specific biologic and prognostic features. The
available genetic modeling provides the best available evidence
that MM is composed of subgroups of patients categorized
according to their underlying genomic aberrations. More
importantly, a comprehensive and accurate understanding of the
genetic nature of MM will ultimately set the platform from which
to develop true targeted therapies. Our efforts have been focused
on the generation and validation of these targets as crucial for
clonal expansion and maintenance. Those fulfilling the last
category should make attractive therapeutic targets.
RF is a Clinical Investigator of the Damon Runyon Cancer
Research Fund. This work was supported in part by Public Health
Service grant no. R01 CA83724-01 (RF) and the Fund to Cure
Myeloma. PRG is supported by the ECOG grant CA21115-25C
from the National Cancer Institute
3. Immunobiology
P3.1
A CELLULAR MODEL FOR MYELOMA CELL GROWTH
AND MATURATION BASED ON CD45 HIERARCHY.
R. Bataille
Laboratory of Hematology, Institute of Biology, 9 quai Moncousu,
44093 Nantes CEDEX 01.
CD45 is a protein tyrosine phosphatase required for lymphocyte
activation and development (1). As soon as its first description as
a leucocyte common antigen, CD45 has been found to be
expressed on B lymphocytes, its expression declining during
plasma-cell differentiation (1, 2). More recently, the variations of
CD45 expression during plasma-cell differentiation have been reevaluated
carefully in vivo by comparing CD45 expression with
that of other antigens on human plasma cells (PC) of different
origins: tonsils, peripheral blood and bone marrow (3). This
important study has first confirmed the existence of a gradient of
increasing maturity of the different human PC compartments
from tonsils to bone marrow through peripheral blood. Second,
with regard to CD45 specifically, a decreasing pattern of
expression was confirmed, with a clear reduction only in bone
marrow PC. This unique true comparative study has confirmed
previous works showing separately either a bright expression of
CD45 on immature PC in tonsils and peripheral blood or a rather
low expression on mature PC inside the bone marrow (4,5,6).
Although these data strongly support the association between a
CD45 bright expression and proliferation in immature PC as
those in tonsils and peripheral blood, contrasting with the downregulation
of CD45 expression observed in the bone marrow
during final maturation, and corresponding to proliferation arrest,
this has never been previously shown directly in vivo.
As soon as 1988, Multiple Myeloma (MM) has been described as
a tumor presenting with either a weak to intermediate expression
of CD45 or even lacking CD45 expression (7). A major advance
in the biology of CD45 in MM has been made by JOSHUA D et
al (8) who demonstrated that CD45 expression was highly
correlated with the proliferation rate of myeloma cells. In this
study, the brightest expression of CD45 was associated with the
highest proliferation rate (labeling index, LI) of myeloma cells.
Furthermore, the proliferation of myeloma cells declined parallel
to that of CD45 expression. Although the restriction of the
highest proliferation to a CD45 bright compartment in MM has
been confirmed by FUJII R et al (9), it was recently disproved by
RAWSTRON A C et al (10) and thus this point remains pending
In the current study, we have evaluated directly the expression of
CD45 on normal and malignant PC of different origins in relation
to their proliferation in vivo. More particularly , we have reevaluated
the expression of CD45 on human myeloma cells in
order to better understand the meaning of CD45 bright and CD45
low myeloma cells and that of the annihilation of CD45 on
myeloma cells .
CD45 expression was evaluated on normal malignant plasma
cells (PC) in relation to their proliferation in vivo (labeling index,
LI). In Tonsils (n=8) and peripheral blood (n=5), all PC were
highly proliferating CD45 bright PC. All reactive plasmocytoses
(n=12) turned out to be homogeneous expansions of this type of
PC with unusually high LI (30%). CD45 bright expression
declines with proliferation arrest and final maturation of PC in
bone marrow only (n=11). In MM (n=37), CD45 expression is
heterogeneous as in normal bone marrow. Proliferation is always
restricted to a minor (12%) CD45 bright population of myeloma
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