Proteomic Analysis of Waldenstrom Macroglobulinemia

Hatjiharissi, Evdoxia; Ngo, Hai T.; Leontovich, Alexey A.; Leleu, Xavier; Timm, Michael; Melhem, Mona F.; George, Diane; Lu, Ganwei; Ghobrial, Joanna; Alsayed, Yazan; Zeismer, Steven C.; Cabanela, Miguel E.; Nehme, Alex; Jia, Xiaoying; Moreau, Anne; Treon, Steven P.; Fonseca, Rafaël; Gertz, Morie A.; Anderson, Kenneth C.; Witzig, Thomas E.; Ghobrial, Irène M.

doi:10.1158/0008-5472.can-06-3089

Cited by 52 publications

(38 citation statements)

References 37 publications

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“…The upregulation of the above proteins was found in both symptomatic and asymptomatic patients, indicating that this deregulation occurs early within disease pathogenesis. 76 Symptomatic disease progression was marked in this study by three proteins: p43/EMAPII, CDC25c, and HSP90. Each of these proteins furthers disease advancement, replication and migration.…”

Section: Proteomic Analysismentioning

confidence: 57%

“…In an analysis performed in 10 WM cases, 6 polypeptides, all of which regulate signal transduction, were found to be dysregulated (>2-fold) in over 60% of cases. 76 Interestingly, Ras family proteins, including p62Dok and Rab4 were up-regulated (Table 3). This increase correlated with the activation of MAPK pathways previously recognized in WM.…”

Section: Proteomic Analysismentioning

confidence: 99%

“…Rho family protein levels were also found to be elevated, suggestive of an increase in adhesive properties of malignant WM cells. 76 Using a lower cut off (>1.3-fold), a much larger number of dysregulated proteins were identified. Notably, cyclin-dependent kinases, regulators of apoptosis, HDAC, and proteins involved in the PI3 kinase pathway were all up-regulated.…”

Section: Proteomic Analysismentioning

confidence: 99%

“…78,81 This agrees with findings of elevated expression of PI3K pathway proteins. 76 While not unique to WM (Akt expression is also increased in MM), constitutive activation results in cell resistance by maintaining cell cycle pathways, inhibiting apoptosis, and supporting proliferation and cell survival.81 Both IL-6 and IGF-1 activate Akt pathways and provide strong targets for therapy. 78 Recently, it was suggested that PTEN negatively regulates this pathway.…”

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confidence: 99%

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Molecular pathogenesis of Waldenstrom's macroglobulinemia

et al. 2012

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Waldenström's macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. While technological advances over the past several decades have dramatically improved the possibilities of studying the molecular basis of Waldenström's macroglobulinemia, the pathogenesis of the disease remains fragmented. Undoubtedly, research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenström's macroglobulinemia is fully revealed. In addition, the low number of in vitro or in vivo models significantly challenges extensive analysis. In this manuscript, we review the molecular basis of this disease.Key words: WM, NF-kB signaling pathway, Jak/STAT, PI3K/Akt, aCGH, IL-6. Waldenström's macroglobulinemia. Haematologica 2012;97(9):1281-1290. doi:10.3324/haematol.2012 This is an open-access paper. Citation: Braggio E, Philipsborn C, Novak A, Hodge L, Ansell S, and Fonseca R. Molecular pathogenesis of ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o nagreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as fever, night sweats or weight loss. The median survival ranges from five to more than ten years, depending on the series analyzed. 10-13The existence of somatic hypermutation in WM indicates a role for antigenic stimulation in the development of WM. [14][15][16] The IgH variable region genes are commonly mutated and the VH3 gene is often used, suggesting antigen exposure and selection. 14,17 Clonality studies have shown clonal IgH and IgL gene rearrangements. The IgH variable region is commonly mutated in WM, but intraclonal variation is usually absent and IgH switching usually does not occur. 18,19 Environmental and inherited factors may contribute to familial IgM-MGUS/WM clusters. Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased risk for progression to WM. 20 In a population-based study of 1,384 individuals with MGUS, researchers showed an increased risk factor of 46 for developing WM. 20 The rate of progression from IgM-MGUS to WM was further noted to be 1.5-2% a year. [21][22][23] While the development of WM is thought to be sporadic, there are a few studies demonstrating familial linkage and predisposition to the disease. 2,[24][25][26] Both familial clustering of WM and a notable increase (~10 fold) of IgM-MGUS frequency in first-degree relatives of WM patients is suggestive of familial risk. 27 Using the assumption that WM and IgM-MGUS share common susceptibility genes, strong linkages involving chromosomes 1q, 3q, and 4q have been identified. 21 A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested b...

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Section: Proteomic Analysismentioning

confidence: 57%

Section: Proteomic Analysismentioning

confidence: 99%

Section: Proteomic Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular pathogenesis of Waldenstrom's macroglobulinemia

et al. 2012

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“…30 We therefore sought to confirm the expression level of phophorylated Akt (phospho-Akt) in WM. As shown in Figure 1A, expression of phospho-Akt was higher in CD19 ϩ WM cells from the BM of 4 patients with WM compared with BM CD19 ϩ cells from 2 healthy donors.…”

Section: Baseline Expression Of Phospho-akt Is Elevated In Patients Wmentioning

confidence: 99%

The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia

Leleu

Jia

Runnels

et al. 2007

Blood

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Proteomic profiling of heat shock proteins: An emerging molecular approach with direct pathophysiological and clinical implications

Bottoni

Giardina

Scatena

2009

Proteomics Clinical Apps

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The HSP family is one of the most ancient and evolutionarily conserved protective protein families found in nature. Originally discovered as inducible molecules capable of maintaining cellular homeostasis against abrupt temperature changes, HSPs were later determined to represent an adaptive physiological response that copes with a variety of different cellular proteotoxic stresses. These physiological molecular chaperones facilitate the synthesis, folding, assembly, trafficking and secretion of specific proteins in various cellular compartments. Most importantly, these proteins guard the whole cell proteome against misfolding and inappropriate aggregation. A series of diversified proteotoxic stresses, including heat, hypoxia/ischemia, free radicals, acidosis, ATP depletion and toxins are capable of inducing a typical cellular stress response characterised by rapid inhibition of overall protein synthesis, with a concomitant dramatic increase in HSP expression. From a pathophysiological point of view, HSP induction has been observed in a wide spectrum of inflammatory and degenerative diseases (from cancer to prion disease by passing to infective and autoimmune diseases) and, intriguingly, overexpression monitoring seems to have potential implications in terms of diagnosis, prognosis and, above all, therapy. Proteomics studies, identifying a series of modification of HSP expression patterns in different diseases, are confirming these promising clinical applications.

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Proteomic Analysis of Waldenstrom Macroglobulinemia

Cited by 52 publications

References 37 publications

Molecular pathogenesis of Waldenstrom's macroglobulinemia

Molecular pathogenesis of Waldenstrom's macroglobulinemia

The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia

Proteomic profiling of heat shock proteins: An emerging molecular approach with direct pathophysiological and clinical implications

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