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What's New In Research - February 5, 2003
02.05.03
A monoclonal Vkappal light chain responsible for incomplete proximal trubulopathy.
Decourt C, Bridoux F, Touchard G, Cogne M.
Laboratoire d'Immunologie et d'Immunogenetique
CNRS UMR 6101, Poitiers, France.
Am J Kidney Dis 2003 Feb;41(2):497-504

ABSTRACT - Calcium and phosphate metabolism abnormalities are frequent in myeloma patients and the role of renal lesions in such ionic perturbations may have been overlooked. The authors herein report the complete primary structure of a Bence Jones Vkappal light chain responsible for myeloma-associated proximal tubulopathy with increased phosphaturia. Plasma and serum biochemical evaluations indicated a proximal tubular dysfunction mainly manifested as tubular acidosis and phosphate loss. The study of a kidney biopsy showed interstitial and tubular lesions with numerous myeloma casts and peculiar features of the proximal tubular cells, which carried numerous phagolysosomal inclusions with occasional crystalline periodic striation. The nephrotoxic light chain primary structure was deduced from the bone marrow monoclonal plasma cells RNA. The kappal sequence was highly homologous to kappa chains previously characterized in patients with Fanconi syndrome. It was related to the Vkappal subgroup and was composed of a variable segment encoded by the O8/O18 germline gene rearranged to Jkappa4. The primary sequence presented unusual features restricted to the variable region, including substitutions of residues 28 and 31 in the complementary determining region 1 (CDR1) by amino acids of different charge. An unusual conformation of the kappal domain, likely resulting from somatic hypermutation, could alter the catabolism of the protein after its internalization and result in the tubular cell dysfunction. Comparison with Fanconi syndrome studies suggests that Vkappal Bence Jones proteins may damage proximal tubular cells to an extent varying according to light chain (LC) sequence and structure, either leading to crystal formation and Fanconi syndrome or inducing partial inhibition of proximal tubule function. Copyright 2003 by the National Kidney Foundation, Inc.


The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma.
Alexandrakis MG, Passam FH, Ganotakis ES, Sfiridaki K, Xilouri I, Perisinakis K, Kyriakou DS.
Division of Medicine, Departments of Haematology, Internal Medicine, Medical Physics, University Hospital of Heraklion, Crete, Department of Haematology, Venizelion General Hospital, Crete, Department of Haematology, University Hospital of Larisa, Thessalia, Greece.
Clin Lab Haematol 2003 Feb;25(1):41-46

ABSTRACT: Interleukin-6 (IL-6) and acute phase proteins are commonly increased in patients with multiple myeloma. Several of these acute phase proteins are believed to predict prognosis and influence survival. We measured interleukin-6 (IL-6), C-reactive protein (CRP), alpha-1-antitrypsin (a1AT), acid alpha-1-glycoprotein (a1AG), haptoglobin (HAP), transferrin (TRF), hemoglobin (Hb), beta-2-microglobulin (beta2M) and erythrocyte sedimentation rate (ESR) in 42 newly diagnosed multiple myeloma patients and 25 normal controls. At the time of blood collection, nine patients were at stage I of disease, 14 at stage II, and 19 at stage III according to the Durie and Salmon myeloma staging system. Mean +/- SD values of IL-6, CRP, a1AT, a1AG, HAP, beta2M, and ESR were significantly higher and Hb significantly lower than those found in the controls. Univariate analysis, using the log-rank test, showed that among the acute phase proteins, serum CRP (P < 0.002), a1AT (P < 0.008) and ESR (P < 0.008) were significantly correlated with survival. However, when a multivariate Cox proportional hazard model was performed, ESR, CRP, a1AT, a1AG and beta2M were identified as independent prognostic factors, while the others were not. We conclude that ESR, a simple and easily performed marker, was found to be an independent prognostic factor for survival in patients with multiple myeloma.


PS-341: prospecting a new hope for myeloma
IMF Scientific Advisor James Berenson, MD of Cedars-Sinai Medical Center; UCLA School of Medicine, reviews the paper by Hideshima and colleagues, Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.
Blood, 15 February 2003, Vol. 101, No. 4, pp. 1210-1210

In this issue, Hideshima and colleagues (page 1530) define the intracellular effects of the proteasome inhibitor PS-341 (Millennium Pharmaceuticals, Cambridge, MA) on myeloma cells. This drug has shown promising activity in early clinical trials for relapsing myeloma patients. Moreover, recent laboratory studies show that exposure to this agent may greatly increase the sensitivity of highly chemotherapy-resistant myeloma cells to the cytotoxic effects of chemotherapy, and have led to clinical trials exploiting this effect for myeloma patients. PS-341 reduces the DNA-binding activity of the transcription factor nuclear factor-kappa B (NF- [kappa ] B) by reducing the degradation of the NF- [kappa ] B inhibitor, I [kappa ] B. In support of this, expression of a dominant-negative vector of I [kappa ] B that is resistant to proteasome-mediated degradation induces apoptosis in both chemotherapy-sensitive and -resistant myeloma cells.

But recent studies, including the Hideshima paper, suggest that other effects of PS-341 may contribute to its antimyeloma effects. This drug has profound effects on TNF, JNK activities, p53, MDM2, DNA protein kinase catalytic subunit (DNA-PKcs), and the ATM proteins. Specifically, exposure to this drug inhibits XIAP, a gene activated by NF- [kappa ] B. This results in enhanced JNK activity, leading to caspase-mediated apoptosis. Other studies have shown that the enhancement of JNK activity by PS-341 is associated with increased TNF production. Indeed, inhibition of TNF reduces the antitumor effects of PS-341. Moreover, this induction of JNK activity also results in activation of caspase-3, leading to cleavage of DNA repair enzymes including DNA-PKcs and ATM, resulting in impaired DNA repair. The proteasome inhibitor also increases p53, resulting in induction of MDM2 expression, as well as enhanced association of these 2 proteins. Ultimately, the activation of caspase-3 leads to p53 phosphorylation and MDM2 degradation, resulting in activation of p53. Thus, the proapoptotic activities of PS-341 on multiple intracellular signaling pathways in myeloma cells results in its potent antitumor effects.

Importantly, furthering our understanding of the intracellular antimyeloma effects of PS-341 will help lead to the development of other drugs that more specifically target these pathways and the exploration of new drug combinations with the potential for enhanced clinical benefits.


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