Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma

Ushmorov, Alexey; Leithäuser, Frank; Sakk, Olena; Weinhäusel, Andreas; Popov, Sergey W.; Möller, Peter; Wirth, Thomas

doi:10.1182/blood-2005-09-3765

Cited by 161 publications

(133 citation statements)

References 62 publications

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“…This observation is consistent with our data in primary HRS cells, where EBF shows lower mRNA expression levels compared to normal B cells. 17 The concerted function of Notch1 in antagonizing E2A and EBF contributes to diminished endogenous expression of the B-cell-specific gene, 36 The critical B-cell commitment factor PAX5 remains expressed in HRS cells despite the general loss of the B-cell phenotype. We demonstrated that Notch1 and PAX5 were coexpressed in primary HRS cells and observed a reciprocal relationship between PAX5 and Notch1 protein expression in cultured HRS and Namalwa cells analyzed in this study.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

et al. 2008

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Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed-Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed-Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma.

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Section: Discussionmentioning

confidence: 99%

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

et al. 2008

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“…This leads to the NPM-ALK fusion gene on the derivative chromosome 5, and to transcription of the chimeric NPM-ALK fusion gene. Translocation involving the ALK gene is found in 90% of paediatric ALCL cases 2 but only in 55% of adult ALCL, 3 raising the hypothesis that this chromosomal abnormality might occur in utero. Previous studies already demonstrated that healthy adults…”

mentioning

confidence: 99%

“…1 Some reports have suggested that epigenetic modifications are involved in this cHL-associated B-cell reprogramming. 2,3 Here, aiming at investigating DNA methylation patterns on a more genome-wide level, we have performed 27K BeadArray analysis 4 in five cHL cell lines. Owing to the low numbers of tumor cells in primary cHL biopsies (B1%), our microarray analyses were restricted to cHL cell lines, which represent widely used models to study this lymphoma.…”

mentioning

confidence: 99%

Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes

et al. 2011

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“…Significantly greater numbers of Syk/Zap-70-positive samples respond to anti-CD33 mAb treatment. 29 Recent discoveries established Syk as a tumor suppressor and linked deficient Syk expression to a variety of human hematopoietic [30][31][32][33] and solid tumors. [33][34][35] In breast cancer, Syk kinase is a potent modulator of malignant growth and a potential tumor suppressor, presumably by controlling cell division.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

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2006

Leukemia

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Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that, upon ligation with a monoclonal antibody (mAb), is a downregulator of cell growth in a Syk-dependent manner. An anti-CD33 mAb coupled to a toxin, gemtuzumab ozogamicin (GO), is used for the treatment of AML (Mylotarg). Therefore, we investigated whether the response of AML cells to GO treatment also depends on Syk expression. Forty primary AML samples (25 Syk-positive and 15 Syk-negative) were tested for their response to the anti-proliferative effects of GO and unmodified anti-CD33 mAb. A correlation between Syk expression and the response of leukemia cells to GO and anti-CD33 mAb was found. 'Blocking' of Syk by small interfering RNA resulted in unresponsiveness of AML cells to both GO and anti-CD33 mAb-mediated cytotoxicity. Syk upregulation by the demethylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, resulting in enhanced GO and anti-CD33-mediated inhibition of leukemia cell growth. Thus, the cytotoxicity of both GO and anti-CD33 in primary AML samples was associated with Syk expression. 5-Aza restored Syk and increased the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. These data have clinical significance for predicting response to GO and designing clinical trials.

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Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma

Cited by 161 publications

References 62 publications

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

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