Haematologica 2003 - Supplements

016
NEUTRAL ENDOPEPTIDASE (CD10) KNOCKOUT MICE
DEVELOP B CELL LYMPHOMAS AND
PLASMACYTOSIS
Scott A. Ely, MD MPH, Daniel M. Knowles, MD
Weill Medical College of Cornell University, New York, NY
BACKGROUND: Neutral endopeptidase (CD10) is a
metalloprotease that reduces the cellular response to certain
peptide hormones. CD10 has been found to play a role in B cell
maturation. However, its precise function and mechanism of
action are unknown. Moreover, the role of CD10 in
lymphomagenesis has not been previously investigated.
DESIGN: CD10 knockout mice (CD10KO) were sacrificed and
autopsied at 6, 10, and 16 months and compared to wild type
(WT) controls for changes in lymphoid compartments and for the
development of tumors. Spleen, bone marrow, thymus, lymph
node and tumor sections were analyzed for morphologic changes
as well as for expression of B220 (CD45R), CD3, CD138, IgG,
IgM, Igκ, and Igλ. Relative numbers of B, T, and plasma cell
subsets (PCs) were compared using image analysis.
RESULTS: At 6 months of age, there were no gross
abnormalities in the mice (3KO and 3 WT). At 10 months, 3
WT mice were phenotypically normal, but 7 of 10 (70%)
CD10KOs had large mesenteric masses that showed follicular
hyperplasia and plasmacytosis, usually marked. At 16 months, 5
WT mice were phenotypically normal but all 5 CD10KOs had
large mesenteric masses: 3 large B cell lymphomas and 2 nodular
lesions, possibly follicular lymphomas. In addition, all the 16
month old CD10KOs had marked marrow IgM plasmacytosis.
The percentage of IgG PCs was markedly reduced.
CONCLUSION: This study shows that CD10 is required for
normal B cell maturation and plasmacytogenesis. It appears that
in the absence of CD10, there is a buildup of IgM PCs with
failure to undergo normal immunoglobulin heavy chain class
switching. In addition, these results suggest that CD10 may
function as a tumor suppressor.
017
Hereditary Multiple Myeloma (MM): An International
Consortium for MM Family Studies
Patrice Watson, Ph.D., Stephano Tarantolo, M.D., Peter H.
Wiernik, M.D., Dennis W. Weisenburger, M.D., David Hogg,
M.D., Ph.D., Brigid Quinn-Laquer, MS, MT, Warren G.
Sanger, Ph.D., Henry T. Lynch, M.D.
Inherited genetic factors in the development of multiple myeloma
(MM) have received limited attention; the rarity of extended MM
families is an obstacle to progress. There have been several
reports describing familial clustering of myeloma within families
however a systematic approaches to delineate a genetic
predisposition is lacking.
We have identified 15 MM families with one or more members
affected with MM. Many of the relatives in these families
present with pancreatic cancer or malignant melanoma. Some of
the families also have members with chronic lymphocytic
leukemia or lymphoma, as well as solid tumors of the colon and
breast. In two of the families, individuals have been diagnosed
with monoclonal gammopathy of unknown significance (MGUS)
in addition to the MM cases. We have collected biological
specimens from 53 individuals in these families. Of the 53
samples, 27 have been tested for CDKN2A (p16) mutations. No
alterations were detected in 26 of these, while one showed an
alteration of unknown significance. We have plans to test all of
the samples and any additional samples from new families for
CDKN2A mutations, as well as, other candidate genes. We also
plan to carry out general linkage studies to localize potential
susceptibility genes.
The occurrence of familial MM is an important phenomenon and
discovery of its genetic basis may illuminate biological pathways
of MM development and contribute to pharmacotherapeutic
advances. However, a sufficient number of informative families
are needed to accomplish these goals. Therefore we propose an
international consortium to study familial MM and invite
interested colleagues to participate. A web site is available,
http://medicine.creighton.edu/HHCC for rapid communication
between members in the consortium.
018
Risk Factors For Multiple Myeloma: A Possible Role
For Breast Implants
Robert A. Vescio,1 Stuart L. Silverman,2 Ann S. Hamilton,3
James R. Berenson,1
1. Dept. of Medicine, Cedars-Sinai Medical Center, Los Angeles,
CA, USA2. Dept. of Preventative Medicine, University of Southern
California, Los Angeles, CA, USA3. Dept. of Medicine, GLA VAHS
and UCLA, Los Angeles, CA, USA
Although autoimmune like symptoms have been attributed to
silicone gel-filled breast implant (SGBI) exposure, few studies
have documented this link. Dr. Potter’s group discovered that
silicone gel removed from commercial mammary implants and
injected intraperitoneally into BALB/c mice induced multiple
myeloma (MM) development at high rates. We subsequently
noted a high incidence of breast implant exposure in our clinical
practice. As a pilot study, serum samples were obtained from a
cohort of 630 women with SGBIs followed in a rheumatology
practice. Elevated quantitative immunoglobulin levels were found
in 23% of the samples and a monoclonal gammopathy was
present in 1.7% of a smaller 284 patient cohort. Consequently, we
initiated a case-control trial to determine the incidence of SGBI
exposure in women diagnosed with MM. California Cancer
Registry data was used to contact women who developed MM
between the years 1991 and 1997. It had been estimated that 91%
of women with SGBIs are < 60 years of age so only such women
were interviewed to reduce study cost. A spouse proxy was
interviewed if available for deceased cases. Cases were asked
about occupational, medical and social history. In order to match
socioeconomic status, controls of similar age and ethnicity were
ascertained by random digit phone dialing using the area code
and prefix of the corresponding case. Up to 5 controls were
interviewed for each of the 208 Caucasian cases. Control women
were required to be within 5 years of age of the case. Spouse
proxies were also interviewed and served as the control for cases
in which a proxy was used. All exposures occurring in the cases
and controls after the date of MM diagnosis were excluded in the
analysis. Breast implant usage was associated with an unadjusted
odds ratio of 2.31 on univariate analysis (95% C.L. 1.01-5.26,
p=0.048). Prior work on a farm, in an airplane, around
microwaves, or use of a computer were also risk factors for MM
development. A higher incidence of complications such as pain
and contracture was noted in the cases with breast implants vs.
controls with breast implants after chi-squared analysis. The
adjusted odds ratio for breast implants with contracture was 4.74
(95% C.L. 1.44-15.68, p=0.01). These results suggest that breast
implant exposure may contribute to the development of MM. A
larger national registry study or prospective analysis of women
currently receiving SGBIs may be required to increase statistical
power and conclusively link or refute this association. The higher
incidence of MM in farm workers has been noted by others and
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