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What's New In Research - September 12, 2003
09.12.03
Plasma cells can turn cancerous by at least six different mechanisms.
© Copyright 2003 Cancer Gene Therapy Week via NewsRx.com

According to recent research from the United States, "An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. "There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane-induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Emu-v-abl), growth factors (IL-6), and anti-apoptotic factors (Bcl-x(L)/Bcl-2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL-6) and cell-cell interactions. In mice, the activation and deregulation of c-myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice," wrote M. Potter and coauthors.

The researchers concluded: "Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far."

Potter and colleagues published their study in Immunological Reviews (Neoplastic development in plasma cells. Immunol Rev, 2003;194(1):177-195).

For additional information, contact M. Potter, NCI, Genetics Laboratory, NIH, 37 convent Dr. MSC4256, Bldg 37, Room 2B04, Bethesda, MD 20892, USA.


More potent drugs against multiple myeloma appear to overcome problems of persistence in bone marrow and drug resistance.
© Copyright 2003 Hematology Week via NewsRx.com

According to a study from the United States, "Multiple myeloma (MM) affects 15000 new patients annually in the US, with 50000 total patients, and remains incurable. "Our preliminary in vitro and animal studies suggest a role for MM-host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow," wrote T. Hideshima and coauthors.

The researchers concluded: "Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS-341, can overcome classical drug resistance in preclinical and early clinical studies."

Hideshima and colleagues published the results of their research in Immunological Reviews (Novel therapeutic approaches for multiple myeloma. Immunol Rev, 2003;194(1):164-176).

For additional information, contact K.C. Anderson, Dana Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, M557, 44 Binney St., Boston, MA 02115, USA.


Effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma.
Ghobrial IM, Dispenzieri A, Bundy KL, Gastineau DA, Rajkumar SV, Therneau TM, Lacy MQ, Witzig TE, Litzow MR, Christensen BR, Hayman S, Pribula CG, Gertz MA.
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester,MN, USA.

Summary:The purpose of this study was to determine the effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma. We performed a retrospective review of 67 patients newly diagnosed with multiple myeloma at Mayo Clinic and treated with a single regimen prior to stem cell transplantation between January of 2000 and September of 2001. Stem cells were collected from 24 patients who received thalidomide, 200 mg/day, with dexamethasone as initial therapy before stem cell collection. These patients were compared with 43 control patients seen during the same period who had received only one previous regimen before stem cell collection and transplantation. The cumulative thalidomide dose before stem cell collection was 17 000 mg over a median of four cycles (range, 2-7 cycles). The thalidomide and control groups were not significantly different in their baseline characteristics, number of stem cells collected, time to collection, or time to engraftment of neutrophils or platelet count of 50 000/microl. Time to platelet count of 20 000/microl was delayed by a median of 4 days (P=0.008), but platelet transfusion requirements did not differ (P=0.95). We concluded that thalidomide does not substantially affect peripheral cell mobilization or engraftment.

Bone Marrow Transplantation (2003) 32, 587-592. doi:10.1038/sj.bmt.1704173


Cornell University; Ig translocations are common, but cyclin D dysregulation occurs in all
© Copyright 2003, Biotech Week via NewsRx.com

Multiple myeloma tumor types have the final effect of dysregulation of cyclin D in common, but not all tumor types are represented in cell lines, as some may need interaction with other cell types to achieve dysregulation.

"Multiple myeloma (MM) is a tumor of long-lived bone marrow plasma cells (PCs). Nearly 40% of MM tumors have immunoglobulin H (IgH) translocations involving 4 recurrent chromosomal loci (oncogenes): 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (MMSET and FGFR3), and 16q23 (c-maf). Other MM tumors have Ig translocations involving different loci, none of which is involved in more than 1% of tumors," scientists in the United States report. "At least 25% of MM tumors have no Ig translocation. Unlike normal PCs, MM tumors usually express 1/3 cyclin D genes at a high level. Translocations involving 4p16 and 16q23 do not directly target a cyclin D gene, but they are associated with a high level of cyclin D2 expression. Although cyclin D1 is not expressed in normal hematopoietic cells, 1/3 of MM tumors ectopically express cyclin D1 in the absence of t(11;14). Despite a low proliferation index in MM, dysregulation of a cyclin D gene seems to be a unifying oncogenic event," wrote P.L. Bergsagel and coauthors from Cornell University.

The researchers concluded: "Analysis of 34 MM cell lines indicates that tumors having an IgH translocation are significantly overrepresented, whereas tumors that ectopically express cyclin D1 are not represented. We speculate that ectopic cyclin D1 expression without t(11;14) is dependent on tumor-specific interaction with bone marrow stromal cells."

Bergsagel and colleagues published their study in Immunological Reviews (Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma. Immunol Rev, 2003;194(1):96-104).

For additional information, contact P.L. Bergsagel, Cornell University, Weill Med College, 1300 York Avenue, Room C615, New York, NY 10021, USA.


The cell cycle plays an integral part in plasma cell biology and dysfunction.
© Copyright 2003 Cancer Weekly via NewsRx.com

According to a study from the United States, "Cell-cycle control is a major determinant of homeostasis during B-cell development, differentiation, and tumorigenesis. The generation of an antibody response requires activation and expansion of antigen-specific B cells and terminal differentiation of these cells into plasma cells. Plasma cells arrest in the G1 phase of the cell cycle, but the mechanism that underlies timely cell-cycle entry and exit in the humoral immune response is not known. "The mammalian cell cycle is regulated primarily at the G1-S transition by the balance between positive regulators, the cyclin-dependent kinases (CDK) together with cyclins; and negative regulators, the CDK inhibitors. One such inhibitor, p18(INK4c), has been shown to be required for cell-cycle termination and final differentiation of nonsecreting plasmacytoid cells into antibody secreting plasma cells. "This finding provides the first direct evidence for cell-cycle control of B-cell immunity. It also raises important questions regarding cell-cycle control of cellular differentiation, apoptosis, and earlier steps of B-cell terminal differentiation," wrote S. Chen-Kiang and coauthors from Cornell University.

The researchers concluded: "This article discusses the biochemical mechanism of cell cycle control in the context of antibody response and plasma cell differentiation, along with the role of cell cycle dysregulation in the pathogenesis of multiple myeloma, the plasma cell cancer."

Chen-Kiang and colleagues published their study in Immunological Reviews (Cell-cycle control of plasma cell differentiation and tumorigenesis. Immunol Rev, 2003;194(1):39-47).

For more information, contact S. Chen-Kiang, Cornell University, Weill Med College, Dept of Pathology, 1300 York Avenue, New York, NY 10021, USA.


Method to predict survival in multiple myeloma developed
© Copyright 2003 Blood Weekly via NewsRx.com

Soluble receptor activator of nuclear factor kappa B ligand-osteoprotegerin ratio predicts survival in multiple myeloma. "Interaction between receptor activator of nuclear factor kappa-B ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival," researchers in England and Greece report. "Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease," said Evangelos Terpos at Imperial College in London and collaborators in England and Greece. "The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRIP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis." "We generated a prognostic index based on these factors that divided our patients into three risk groups," reported the researchers. "The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively.

Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development Of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival."

Terpos and associates published their study in Blood (Soluble receptor activator of nuclear factor kappa B ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood, 2003;102(3):1064-1069).

For additional information, contact Evangelos Terpos, Hammersmith Hospital, Imperial College Faculty of Medicine, Department of Hematology, Du Cane Road, London W12 0NN, UK. E-mail: e.terpos@imperial.ac.uk.


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