|
 Previous Article | Table of Contents | Next Article 
Circulating monoclonal B cells expressing P glycoprotein may be a reservoir
of multidrug-resistant disease in multiple myeloma
LM Pilarski and AR Belch
Department of Immunology, University of Alberta, Edmonton, Canada.
Multiple myeloma is basically an incurable cancer. Most patients respond
initially to chemotherapy with reduction in bone marrow (BM) plasma cells
and monoclonal Ig levels, but the disease nearly always recurs and becomes
refractory to therapy. The objective of this study was to characterize the
expression of the multidrug transport pump, P- glycoprotein 170 (P-gp), in
myeloma. The great majority of B cells from peripheral blood mononuclear
cells (PBMCs) in myeloma express P-gp, detected by the monoclonal antibody
MRK-16. P-gp+ blood B cells exhibit extensive DNA hyperdiploidy, suggesting
replicative abnormality characteristic of malignant growth. We speculate
these represent a stem cell population in myeloma. The proportion of B
cells expressing P-gp was comparable among untreated myeloma patients and
those treated with chemotherapy, biologic response modifiers, or off
treatment. Among BM cells, P-gp was absent or low in untreated myeloma
patients but was expressed at high levels on BM cells from patients
previously treated with chemotherapy. For untreated patients the majority
of B/plasma cells expressing P-gp are located in PBMCs, not the BM cells.
Flow cytometric analysis of rhodamine 123 dye efflux indicated a functional
P-gp that was efficiently blocked by verapamil or cyclosporin A (CsA). Both
the CD11bhi CD19+ B cells and the T cells in myeloma PBMCs had active
CsA-inhibited dye efflux, but monocytes lacked the ability to efflux dye.
Nearly all CD38hi plasma cells from myeloma BM cells retained dye,
indicating their lack of a functional transport pump. Thus, PBMC B cells
may be the predominant set of drug-resistant tumor cells. Myeloma PBMC B
cells were cultured with Adriamycin with or without CsA and drug toxicity
evaluated by the induction of apoptosis, using flow cytometry to quantitate
DNA disruption. No apoptosis was detectable at 0.01 microgram/mL
adriamycin, the in vivo steady-state level, with or without CsA. With 0.1
microgram adriamycin, no apoptosis was detectable in the absence of CsA,
but with CsA, 66% of B cells initiated DNA disruption, whereas most T cells
were spared. This work suggests that currently used drug dosages are too
low to effect P-gp+ B- cell death, even in the presence of CsA. We suggest
that blood B cells comprise a highly drug-resistant subset of the myeloma B
lineage that escapes conventional chemotherapy and may underlie the almost
uniform fatal relapse in myeloma patients.
Volume 83,
Issue 3,
pp. 724-736,
02/01/1994
Copyright © 1994 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. O. Abdalla, P. Kokhaei, L. Hansson, H. Mellstedt, and A. Osterborg
Idiotype vaccination in patients with myeloma reduced circulating myeloma cells (CMC)
Ann. Onc.,
February 13, 2008;
(2008)
mdn017v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Sapra, R. Stein, J. Pickett, Z. Qu, S. V. Govindan, T. M. Cardillo, H. J. Hansen, I. D. Horak, G. L. Griffiths, and D. M. Goldenberg
Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys
Clin. Cancer Res.,
July 15, 2005;
11(14):
5257 - 5264.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Huang, H.-F. Tien, F.-H. Su, and S.-M. Hsu
Nonirradiated NOD/SCID-Human Chimeric Animal Model for Primary Human Multiple Myeloma: A Potential in Vivo Culture System
Am. J. Pathol.,
February 1, 2004;
164(2):
747 - 756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Pilarski and A. R. Belch
Clonotypic Myeloma Cells Able to Xenograft Myeloma to Nonobese Diabetic Severe Combined Immunodeficient Mice Copurify with CD34+ Hematopoietic Progenitors
Clin. Cancer Res.,
October 1, 2002;
8(10):
3198 - 3204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Taylor, J. A. Pittman, K. Seeberger, M. J. Mant, T. Reiman, A. R. Belch, and L. M. Pilarski
Intraclonal Homogeneity of Clonotypic Immunoglobulin M and Diversity of Nonclinical Post-Switch Isotypes in Multiple Myeloma: Insights into the Evolution of the Myeloma Clone
Clin. Cancer Res.,
February 1, 2002;
8(2):
502 - 513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. W. Cremer, H. Goldschmidt, M. Moos, T. Rasmussen, and H. E. Johnsen
Clonotypic B cells in the peripheral blood of patients with multiple myeloma
Blood,
May 1, 2001;
97(9):
2913 - 2914.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Rasmussen, L. Jensen, L. Honore, and H. E. Johnsen
Frequency and kinetics of polyclonal and clonal B cells in the peripheral blood of patients being treated for multiple myeloma
Blood,
December 15, 2000;
96(13):
4357 - 4359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Pilarski, N. V. Giannakopoulos, A. J. Szczepek, A. M. Masellis, M. J. Mant, and A. R. Belch
In Multiple Myeloma, Circulating Hyperdiploid B Cells Have Clonotypic Immunoglobulin Heavy Chain Rearrangements and May Mediate Spread of Disease
Clin. Cancer Res.,
February 1, 2000;
6(2):
585 - 596.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. M. Pilarski, G. Hipperson, K. Seeberger, E. Pruski, R. W. Coupland, and A. R. Belch
Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice
Blood,
February 1, 2000;
95(3):
1056 - 1065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby and J. Epstein
The Proliferative Potential of Myeloma Plasma Cells Manifest in the SCID-hu Host
Blood,
November 15, 1999;
94(10):
3576 - 3582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Crainie, A. R. Belch, M. J. Mant, and L. M. Pilarski
Overexpression of the Receptor for Hyaluronan-Mediated Motility (RHAMM) Characterizes the Malignant Clone in Multiple Myeloma: Identification of Three Distinct RHAMM Variants
Blood,
March 1, 1999;
93(5):
1684 - 1696.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Shiokawa, J. Nishimura, K. Ohshima, N. Uike, and K. Yamamoto
Establishment of a Novel B Cell Clonality Analysis Using Single-Strand Conformation Polymorphism of Immunoglobulin Light Chain Messenger Signals
Am. J. Pathol.,
November 1, 1998;
153(5):
1393 - 1400.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Szczepek, K. Seeberger, J. Wizniak, M. J. Mant, A. R. Belch, and L. M. Pilarski
A High Frequency of Circulating B Cells Share Clonotypic Ig Heavy-Chain VDJ Rearrangements With Autologous Bone Marrow Plasma Cells in Multiple Myeloma, as Measured by Single-Cell and In Situ Reverse Transcriptase-Polymerase Chain Reaction
Blood,
October 15, 1998;
92(8):
2844 - 2855.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby, B. Barlogie, and J. Epstein
Primary Myeloma Cells Growing in SCID-hu Mice: A Model for Studying the Biology and Treatment of Myeloma and Its Manifestations
Blood,
October 15, 1998;
92(8):
2908 - 2913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Szczepek, P.L. Bergsagel, L. Axelsson, C. B. Brown, A. R. Belch, and L. M. Pilarski
CD34+ Cells in the Blood of Patients With Multiple Myeloma Express CD19 and IgH mRNA and Have Patient-Specific IgH VDJ Gene Rearrangements
Blood,
March 1, 1997;
89(5):
1824 - 1833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
