Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma

Armellini, Adriana; Sarasquete, María Eugenia; Chillón, María Carmen; Balanzategui, Ana; Alcoceba, Miguel; Fuertes, Marta; López, Rafael; Hernández, José; Fernández-Calvo, J.; Sierra, Magdalena; Megido, Marta; Órfão, Alberto; Gutiérrez, Norma C.; González, Marcos; Miguel, Jesús F. San

doi:10.1111/j.1365-2141.2007.06956.x

Cited by 28 publications

(39 citation statements)

References 13 publications

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“…In HL HLXB9 and HOXB9 have been identified as downstream targets of aberrant PI3K-and ERK5-signaling, respectively (Nagel et al, 2005(Nagel et al, , 2007. Expression of homeobox gene ZHX2 is deregulated in MM and DLBCL (Harousseau et al, 2004;Hystad et al, 2007;Armellini et al, 2008), however, the mechanisms of deregulation and its pathologic function remained unknown. In MM low expression levels of ZHX2 are associated with poor prognosis, indicating tumor suppressor activity.…”

Section: Discussionmentioning

confidence: 98%

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t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Nagel

Schneider

Rosenwald

et al. 2011

Genes Chromosomes & Cancer

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Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.

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Section: Discussionmentioning

confidence: 98%

“…Deregulated expression has been described in MM and DLBCL. Moreover, in MM low ZHX2 levels have been connected with poor prognosis, indicating tumor suppressor activity in this B-cell malignancy (Harousseau et al, 2004;Armellini et al, 2008;Hystad et al, 2007).…”

Section: Breakpoint At 8q24 Targets Homeobox Gene Zhx2mentioning

confidence: 99%

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Nagel

Schneider

Rosenwald

et al. 2011

Genes Chromosomes & Cancer

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“…Shaughnessy et al 33 found that low expression of ZHX2 was associated with a risk of progression in a selected series of 221 transplanted patients with MM. In addition, lower expression of ZHX2 protein was detected in high-risk proliferative MM than in low-risk proliferative MM, 34 and the expression level of ZHX2 protein was closely related with the invasion ability of MM. 35 Some properties of ZHX2 are taken into an important prognostic marker for MM.…”

Section: Hematological Diseasesmentioning

confidence: 96%

“…The increased ZHX2 mRNA level was associated with beneficial prognostic index like β 2 -microglobulin o 5.5 mg l − 1 , albumin 435 g l − 1 or a better cytogenetics. 34 Furthermore, high expression level of ZHX2 correlated with prolonged duration of response and overall survival of patients. 34 In addition, the patients with low ZHX2 levels had a higher rate of resistance to chemotherapy.…”

Section: Hematological Diseasesmentioning

confidence: 99%

“…34 Furthermore, high expression level of ZHX2 correlated with prolonged duration of response and overall survival of patients. 34 In addition, the patients with low ZHX2 levels had a higher rate of resistance to chemotherapy. 34 Expression analysis in hematopoietic cell lines and primary cells indicated that B-cell-specific homeobox gene ZHX2 is a tumor suppressor gene in Hodgkin lymphoma.…”

Section: Hematological Diseasesmentioning

confidence: 99%

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Zinc fingers and homeoboxes family in human diseases

Liu

2015

Cancer Gene Ther

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The zinc-fingers and homeoboxes (ZHX) family is a group of nuclear homodimeric transcriptional repressors that interact with a subunit of nuclear factor-Y (NF-YA) and contain two C2H2-type zinc fingers and five homeobox DNA-binding domains. The members of ZHX family form homodimers or heterodimers with other members or a subunit of NF-YA to repress transcription. ZHX family members function in hematopoietic cell development and differentiation, and neural progenitor maintenance. Dysfunction of ZHX family members correlates with the development and progression of various diseases, including hepatocellular carcinoma (HCC), hematological diseases, neurological diseases and glomerular diseases. Furthermore, low expression of ZHX is associated with poor prognosis in malignancies. This review provides an update on the role of ZHX family in development and its function in cancer, with special emphasis on HCC and hematological malignant diseases.

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Deregulated FOX genes in Hodgkin lymphoma

Nagel

Meyer

Kaufmann

et al. 2014

Genes Chromosomes & Cancer

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FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

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Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma

Cited by 28 publications

References 13 publications

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Zinc fingers and homeoboxes family in human diseases

Deregulated FOX genes in Hodgkin lymphoma

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