Clinical Significance of Intracytoplasmic nm23-H1 Expression in Diffuse Large B-Cell Lymphoma

Niitsu, Nozomi; Nakamine, Hirokazu; Okamoto, Masanori; Akamatsu, Hiroko; Higashihara, Masaaki; Honma, Yoshio; Okabe‐Kado, Junko; Hirano, Masami

doi:10.1158/1078-0432.ccr-03-0085

Cited by 29 publications

(25 citation statements)

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“…The level of nm23-H1 expression was inversely correlated with the metastatic potential of tumors in experimental rodent cells and in human tumors, such as ovarian, breast, and cervical tumors, and melanomas (15). On the contrary, the opposite trend has been reported in thyroid carcinoma, neuroblastoma, and non-Hodgkin's lymphoma, although the mechanism of this discrepancy is unknown (5)(6)(7)16). We previously reported cytoplasmic nm23-H1 expression in DLBCLs (7) and Hodgkin's lymphomas (10) and found that the serum and cytoplasmic nm23-H1 levels were significant prognostic factors in both DLBCLs and Hodgkin's lymphomas.…”

Section: Discussionmentioning

confidence: 99%

“…We previously established an ELISA technique for determination of the serum level of nm23-H1 protein (5,6) and reported that the serum level of nm23-H1 in patients with aggressive lymphoma was significantly higher than that in healthy controls and that a high nm23-H1 level was associated with poor prognosis in aggressive lymphoma (5). In our previous immunohistochemical study on cytoplasmic nm23-H1 expression in diffuse large B-cell lymphoma (DLBCL), we found that patients with positive cytoplasmic staining had significantly poorer prognosis than patients with negative staining (7).…”

Section: Introductionmentioning

confidence: 91%

“…The expression of nm23-H1 and TIA-1 by lymphoma cells was examined immunohistochemically on formalinfixed, paraffin-embedded sections by the avidin-biotinperoxidase complex method (7,10). Monoclonal antibodies to nm23-H1 (clone 37.6, Novocastra Laboratories, Ltd; clone H1-229, Seikagaku Corporation) were used as primary reagents.…”

Section: Morphologic and Immunophenotypic Studiesmentioning

confidence: 99%

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Expression of nm23-H1 Is Associated with Poor Prognosis in Peripheral T-Cell Lymphoma, Not Otherwise Specified

Niitsu

Nakamine

Okamoto

2011

Clinical Cancer Research

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Purpose: We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS).Experimental Design: We studied 102 consecutive, untreated PTCL-NOS patients from 1998 to 2008. The expression of nm23-H1 and TIA-1 was studied by immunohistochemistry.Results: nm23-H1 was positive in 44.1% and TIA-1 in 78.4% of the PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage but was significantly correlated with the prognostic index for T-cell lymphoma. The serum nm23-H1 level was 43.44 ng/mL in the cytoplasmic nm23-H1 strongly positive, 24.32 ng/mL in the cytoplasmic nm23-H1 moderately positive, and 13.64 ng/mL in the cytoplasmic nm23-H1-negative patients. The nm23-H1-positive group had significantly shorter overall survival (OS). TIA-1 had no prognostic impact on 5-year OS rates. OS was significantly shorter in patients with the following clinicopathologic features: age 60 or more years, PS of 2 to 4, LDH level greater than normal, bone marrow involvement, or nm23-H1-positive lymphoma. Multivariate analysis confirmed nm23-H1 expression to be an independent prognostic factor.Conclusions: The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggested that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Morphologic and Immunophenotypic Studiesmentioning

confidence: 99%

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Expression of nm23-H1 Is Associated with Poor Prognosis in Peripheral T-Cell Lymphoma, Not Otherwise Specified

Niitsu

Nakamine

Okamoto

2011

Clinical Cancer Research

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“…In acute myeloid leukemia (AML) and high-grade lymphoma, Nm23-H1 and -H2 are often overexpressed and correlate with patient white cell count, and decreased overall patient survival (7)(8)(9). Nm23-H1 and -H2 are highly expressed in normal CD34 þ hemopoietic progenitors, but are downregulated during normal hemopoietic maturation (10).…”

Section: Introductionmentioning

confidence: 99%

Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone

et al. 2011

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Nm23-H1 plays complex roles in the development of diverse cancers including breast carcinoma, high-grade lymphomas, and acute myeloid leukemia (AML). In the case of AML and lymphomas, serum Nm23-H1 protein is elevated with the highest levels correlating with poorest prognosis. A recent study identified that this association is most likely causal in AML and that Nm23-H1 acts as an AML cell survival factor. In this study, we report heterogeneity in the ability of AML samples to bind and respond to Nm23-H1, and we offer evidence that binding is essential for improved survival. Further, we show that the subset of AMLs that bind Nm23-H1 do not do so through the putative Nm23-H1 receptor MUC1*. Although rNm23-H1 promoted the survival of the most primitive blasts within responding AMLs, it was not these cells that actually bound the protein. Instead, rNm23-H1 bound to more mature CD34 lo /CD34 À and CD11b þ cells, revealing an indirect survival benefit of Nm23-H1 on primitive blasts. In support of this finding, the survival of purified blast cells was enhanced by medium conditioned by more mature cells from the clone that had been stimulated by rNm23-H1. Levels of interleukin 1b (IL1b) and IL6 in rNm23-H1 conditioned medium mirrored the potency of the conditioned media to promote blast cell survival. Furthermore, Nm23-H1 expression was significantly associated with IL1b and IL6 expression in primary uncultured AML samples. These findings have implications for the role of Nm23-H1 in AML and its use as a prognostic marker. Additionally, they offer the first evidence of novel cross-talk between cell populations within the tumor clone. Cancer Res; 71(3); 1177-86. Ó2010 AACR.

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“…Published data suggest that altered Nm23-H1 expression correlates with tumor progression and outcomes (7,13,16,22,26,35,48). However, these data are conflicting, with some studies suggesting that reduced Nm23-H1 expression leads to tumor progression and reduced patient survival (7,16,22,35), while others suggest that increased Nm23-H1 expression portends reduced survival (13,26,48). Therefore, Nm23-H1 regulation of pathogenesis may be tumor specific, and identification of regulatory mechanisms for Nm23-H1 expression and cellular localization would facilitate a better understanding of type-specific, Nm23-H1-associated cancer progression.…”

mentioning

confidence: 99%

Regulation of Nm23-H1 and Cell Invasiveness by Kaposi's Sarcoma-Associated Herpesvirus

Qin

Dai

Toole

et al. 2011

J Virol

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The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and the induction of an invasive cellular phenotype by KSHV following de novo infection is an important pathogenic component mediating tumor progression. The metastasis suppressor gene known as Nm23-H1 regulates tumor cell invasiveness, but whether KSHV itself regulates Nm23-H1 expression or subcellular localization, and whether this impacts cell invasiveness, has not been established. We found that KSHV increases expression and nuclear translocation of Nm23-H1 and that nuclear translocation of Nm23-H1 is regulated by the KSHV-encoded latency-associated nuclear antigen (LANA). Moreover, activation of the Ras-BRaf-MAPK (mitogen-activated protein kinase) signal transduction pathway, secretion of promigratory factors associated with this pathway, and cell invasiveness are dependent on KSHV regulation of Nm23-H1. Finally, induction of cytoplasmic overexpression of Nm23-H1 using a pharmacologic inhibitor of DNA methylation reduced KSHVassociated Ras-BRaf-MAPK pathway activation and suppressed KSHV-induced invasiveness. These data provide the first evidence for KSHV regulation of Nm23-H1 as a mechanism for KSHV induction of an invasive cellular phenotype and support the potential utility of targeting Nm23-H1 as a therapeutic approach for the treatment of KS.The Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) (8). Despite the reduced incidence of HIV-associated KS in the era of highly active antiretroviral therapy (HAART) (49), KS still represents one of the most common HIV-associated tumors in the modern era (6, 11) and an important cause of morbidity and mortality in patients receiving solid organ transplants (21). Acquisition of a migratory or invasive phenotype represents one hallmark of KSHV-infected cells and an important pathogenic mechanism for KS formation (29). A better understanding of KSHV-host cell interactions regulating cell invasiveness may help to identify mechanisms for KS pathogenesis and novel therapeutic targets.Acquisition of an invasive phenotype is negatively regulated by metastasis suppressor genes (MSGs), and over 20 MSGs have been identified to date (17, 34). The first well-characterized MSG, a histidine kinase known as Nm23-H1 (41), inhibits metastasis through cooperative mechanisms, including the phosphorylation of key intracellular proteins regulating signal transduction and the alteration of gene expression (42). Published data suggest that altered Nm23-H1 expression correlates with tumor progression and outcomes (7,13,16,22,26,35,48). However, these data are conflicting, with some studies suggesting that reduced Nm23-H1 expression leads to tumor progression and reduced patient survival (7,16,22,35), while others suggest that increased Nm23-H1 expression portends reduced survival (13,26,48). Therefore, Nm23-H1 regulation of pathogenesis may be tumor specific, and identification of regulatory mechanisms for Nm23-H1 expression and cellular locali...

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Clinical Significance of Intracytoplasmic nm23-H1 Expression in Diffuse Large B-Cell Lymphoma

Cited by 29 publications

References 24 publications

Expression of nm23-H1 Is Associated with Poor Prognosis in Peripheral T-Cell Lymphoma, Not Otherwise Specified

Expression of nm23-H1 Is Associated with Poor Prognosis in Peripheral T-Cell Lymphoma, Not Otherwise Specified

Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone

Regulation of Nm23-H1 and Cell Invasiveness by Kaposi's Sarcoma-Associated Herpesvirus

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