BM MICROVESSEL ENDOTHELIAL CELLS IN MM
HARBOR MYELOMA-ASSOCIATED
CHROMOSOMAL TRANSLOCATIONS
10th INTERNATIONAL MYELOMA WORKSHOP
SYDNEY
CHAIRMAN`S SYMPOSIUM
BM ANGIOGENESIS IS A HALLMARK OF MM BIOLOGY
HIGH BM MVD CORRELATES
INCREASED BM MVD
WITH SHORT SURVIVAL
IHC - CD34 staining
Kumar et al, BMT 2004;34:235
HYPOTHESIS
· Endothelial cells in the BM of patients with MM differ from
their normal counterparts with respect to
morphology
antigen expression
function
they ressemble tumor endothelial cells
Vacca et al., Blood 102;3340-8 (2003)
· Based upon differences between tumor and normal endothelial
cells, we hypothesized that there may be genotypic alterations
as well
ENDOTHELIAL CELLS IN B-CELL LYMPHOMAS HARBOR
IgH TRANSLOCATIONS
t(14;18)
t(11;14)
Streubel B, et al., NEJM 351: 250 (2004)
FICTION
Fluorescence immunophenotyping &
Interphase cytogenetics
Endothelial cell specific markers:
· anti-CD31, anti-CD34, anti-von Willebrand factor,
Ulex europaeus lectin
· at least 2 markers were stained per case
200 microvascular endothelial cells were analyzed per slide
BM ENDOTHELIAL CELLS IN
MULTIPLE MYELOMA
4 patients with a t(11;14)(q13;q32)
1 patient with a t(4;14)(p16;q32)
Tumor-specific genetic aberrations in 21 71%
(median 42%) of BM endothelial cells
CD31
11q13 (cyclinD1)
14q32 (IgH)
Bone marrow biopsy of MM with t(11;14)
Multiple myeloma endothelial cells
Antibody against CD31 and a probe for
centromere 9
Hematological Malignancies
Cases (n=21)
% ECs with aberration
4 chronic B-cell leukemias
+12
14-27
6 anaplastic large cell lymphomas
t(2;5)
10-30
1 peripheral T- cell lymphoma
+7,+7
43
4 chronic myeloid leukemias
t(9;22)
37-84
4 acute myeloid leukemias
t(15;17); t(8;21); t(11;19); +8
21-40
1 pre-B-ALL
t(4;11)
16
Peripheral T-cell lymphoma with an antibody
against CD31 and a probe for centromere 7
Tumor cell
Endothelial cell
FREQUENCIES OF ABERRANT ENDOTHELIAL CELLS
%
63%
60
50
42%
40
37%
30
20
20%
16%
10
CML
MM
B-NHL
CLL
LARGE CELL
ANAPLASTIC L.
Solid Tumors
Tumors (n=32)
% ECs with aberration
6 Breast carcinomas
amp(Her-2/neu)
0
4 Papillary renal cell carcinomas
+7,+17
0
5 Ewing sarcomas
t(11;22)
0
4 Oligodendrogliomas
1p36-/19q13-
0
5 Glioblastomas
+7
0
8 Melanomas
miscellaneous
10-40
Melanoma with gain of chromosome 1
(antibody against CD31 and probes
for centromere 1 and centromere 18)
Cultured endothelial cells of a follicular lymphoma:
Antibody against CD31 (a) and vWF (b) and vWF and
probes for IGH and BCL2 (c) centromere 7 (d)
Cultured cells of a follicular lymphoma after stimulation
with TNF : antibody against E-Selectin, centromere 7
Melanoma
with
trisomy 18:
Cultured
endothelial
cells with
an
antibody
against
CD31and
probes for
centromere
1 and
centromere
18
SUMMARY
· Tumor specific chromosomal aberrations in microvessel
endothelial cells
YES: Myeloma and other hematological malignancies;
malignant melanoma
NO: Breast, renal, bone & brain tumors
· Endothelial cells with tumor specific aberrations can be
propagated in vitro
· These results point to a novel aspect of tumor angiogenesis
Aberrant tumor microvessels
Cooperating Institutions at the Medical University of Vienna
Laboratory Medicine: I. Schwarzinger, M.Exner,
H.Esterbauer, O.Wagner
Pathology: B.Streubel, D.Huber, A.Chott
Internal Medicine I/Hematology & Oncology: J.Drach,
U.Jäger, P.Valent
Dermatology: Ch. Höller, H.Pehamberger
Document Outline