ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia

Rassenti, Laura Z.; Huynh, Loc T.; Toy, Tracy L.; Chen, Liguang; Keating, Michael J.; Gribben, John G.; Neuberg, Donna; Flinn, Ian W.; Kanti, R.; Byrd, John C.; Kay, Neil E.; Greaves, Andrew W.; Weiss, Arthur; Kipps, Thomas J.

doi:10.1056/nejmoa040857

Cited by 818 publications

(830 citation statements)

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“…7C). The correlations between SHM and ZAP70 with clinical state are in agreement with studies presented by others [27,28]. Thus CLL severity correlated with ZAP70 staining and SHM but not with Igb mRNA expression.…”

Section: Correlations Of the Molecular Determinants Of Cll With Clinisupporting

confidence: 92%

“…We next assessed the relationship between Igb mRNA expression and ZAP70 expression, another reported parameter of CLL severity and prognosis [21][22][23][24][25][26][27][28]. An immunohistochemical assay of ZAP70 protein expression in peripheral lymphocytes was developed for this purpose.…”

Section: Comparison Of Igb Mrna Expression With Zap70 Stainingmentioning

confidence: 99%

“…The Igb mRNA expression levels in the CLL cells were compared to two recently identified benchmark parameters of CLL severity, somatic hypermutation (SHM) status of the immunoglobulin variable heavy chain (IgV H ) gene and ZAP70 protein expression [21][22][23][24][25][26][27][28]. We report a significant correlation between Igb mRNA levels and the SHM status in CLL.…”

Section: Introductionmentioning

confidence: 99%

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Igβ(CD79b) mRNA expression in chronic lymphocytic leukaemia cells correlates with immunoglobulin heavy chain gene mutational status but does not serve as an independent predictor of clinical severity

et al. 2007

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The etiology of chronic lymphocytic leukemia (CLL) is poorly understood and its course is highly variable. Somatic hypermutation (SHM) of the immunoglobulin heavy chain (IgV H ) gene and ZAP70 protein expression have been reported as prognostic indicators. However, these assays are not widely available and their concordance is imperfect. Thus a need exists to identify additional molecular determinants of CLL. The Igb (CD79b) subunit of the B cell antigen receptor is essential for B lymphocyte function. Defects in Igb expression are implicated in CLL pathogenesis. We have analyzed Igb mRNA expression in CLL cells in 40 consecutive patient samples. About 75% of the samples showed the expected decrease of Igb surface staining. Igb mRNA levels covered a wider range, did not correlate with Igb surface staining, but clearly distinguished the normal and CLL lymphocyte populations. Remarkably, Igb mRNA levels correlated strongly with SHM; Igb mRNA levels in CLL cells were significantly higher in patients with an unmutated IgV H gene when compared with those in whom IgV H was hypermutated (P 5 0.008). In contrast, no correlation was observed between Igb mRNA levels and ZAP70 expression. Multiple parameters abstracted from chart reviews were used to estimate severity of CLL in each case. While severity correlated strongly with ZAP70 staining, and to a lesser extent with SHM status, there was no correlation with Igb mRNA levels. These data establish a strong linkage between Igb mRNA expression and SHM in CLL and highlight the complex relationships between biochemical parameters and clinical status in this disease. Am. J. Hematol. 82:712-720, 2007. V

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Section: Correlations Of the Molecular Determinants Of Cll With Clinisupporting

confidence: 92%

Section: Comparison Of Igb Mrna Expression With Zap70 Stainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Igβ(CD79b) mRNA expression in chronic lymphocytic leukaemia cells correlates with immunoglobulin heavy chain gene mutational status but does not serve as an independent predictor of clinical severity

et al. 2007

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“…Such studies have led to the identification of a number of prognostic biomarkers. These include IgV H mutation status (Damle et al, 1999;Hamblin et al, 1999), CD38 expression (Damle et al, 1999;Hamblin et al, 1999), ZAP-70 expression (Crespo et al, 2003;Orchard et al, 2004;Rassenti et al, 2004), chromosomal abnormalities (Dohner et al, 2000) and functional abnormalities of the p53 pathway (Lin et al, 2002). Among the prognostic biomarkers so far identified, the most powerful predictor of short survival is mutation or deletion of the TP53 gene, which encodes p53 (el Rouby et al, 1993;Wattel et al, 1994;Dohner et al, 1995;Lens et al, 1997;Cordone et al, 1998;Oscier et al, 2002;Thornton et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

et al. 2007

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In chronic lymphocytic leukaemia (CLL), mutation/ deletion of TP53 is strongly associated with early disease progression, resistance to chemotherapy and short patient survival. Consequently, there is a pressing need to develop novel treatment protocols for this high-risk patient group. The present study was performed to evaluate Hsp90 inhibition as a possible therapeutic approach for such patients. Primary CLL cells of defined ataxia telangiectasia mutated (ATM)/p53 status were incubated with the Hsp90 inhibitor geldanamycin (GA) and analysed by western blotting for the expression of p53, p21, MDM2 and Akt. GA downregulated overexpressed mutant p53 protein (an oncogene) and upregulated wild-type (wt) p53 (a tumour suppressor). The upregulation of wt p53 by GA was independent of ATM and was accompanied by downregulation of Akt and the active form of MDM2, indicating a possible mechanism. GA also produced a p53/ ATM-independent increase in the levels of p21-a potent inducer of cell-cycle arrest. In-vitro cytotoxicity studies showed that GA killed cultured CLL cells in a dose-and time-dependent fashion irrespective of their p53/ATM status and more effectively than normal blood mononuclear cells. In summary, our findings reveal important consequences of inhibiting Hsp90 in CLL cells and strongly support the therapeutic evaluation of Hsp90 inhibitors in poor-prognosis patients with p53 defects.

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“…Patients with CLL cells expressing mutated immunoglobulin V H genes (M-CLL) have a good prognosis, whereas those whose CLL cells express unmutated V H genes (U-CLL) have a more aggressive disease with poorer clinical outcome and require more treatment [18,19]. Gene expression profiling has identified key differences between these two disease subtypes and, remarkably, expression of Zap70 is the strongest predictor of the aggressive subtype with poor clinical outcome [20][21][22]. While most M-CLL cases do not express Zap70, a majority of U-CLL cases express the kinase.…”

Section: Introductionmentioning

confidence: 99%

Redundant role for Zap70 in B cell development and activation

Fallah-Arani

Schweighoffer²,

Vanes³

et al. 2008

Eur J Immunol

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Expression of the Syk family tyrosine kinase Zap70 is strongly correlated with poor clinical outcome in chronic lymphocytic leukemia, the most common human leukemia characterized by B cell accumulation. The expression of Zap70 may reflect the specific cell of origin of the tumor or may contribute to pathology. Thus, the normal role of Zap70 in B cell physiology is of great interest. While initial studies reported that Zap70 expression in the mouse was limited to T and NK cells, more recent work has shown expression in early B cell progenitors and in splenic B cells, suggesting that the kinase may play a role in the development or activation of B cells. In this study, we show that Zap70 is expressed in all developing subsets of B cells as well as in recirculating B cells, marginal zone B cells and peritoneal B1 cells. Analysis of Zap70-deficient mice shows no unique role for Zap70 in either the development of B cells or in their in vitro and in vivo activation. However, we show that Zap70 can rescue the defective positive selection of immature B cells into the recirculating pool in Syk-deficient mice, demonstrating functional redundancy between these two kinases.

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ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia

Abstract: Although the presence of an unmutated IgV(H) gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

Cited by 818 publications

References 23 publications

Igβ(CD79b) mRNA expression in chronic lymphocytic leukaemia cells correlates with immunoglobulin heavy chain gene mutational status but does not serve as an independent predictor of clinical severity

Igβ(CD79b) mRNA expression in chronic lymphocytic leukaemia cells correlates with immunoglobulin heavy chain gene mutational status but does not serve as an independent predictor of clinical severity

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

Redundant role for Zap70 in B cell development and activation

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