Cyclin D1 expression in Rosai-Dorfman disease: a near-constant finding that is not invariably associated with mitogen-activated protein kinase/extracellular signal–regulated kinase pathway activation

Garcés, Sofía; Medeiros, L. Jeffrey; Marques‐Piubelli, Mario L.; Siqueira, Sheila Aparecida Coelho; Miranda, Roberto N.; Cuglievan, Branko; Sriganeshan, Vathany; Medina, Ana Maria; Garcés, Juan Carlos; Saluja, Karan; Bhattacharjee, Meenakshi B.; Khoury, Joseph D.; Li, Shaoying; Xu, Jie; Jelloul, Fatima Zahra; Thakral, Beenu; Yin, C. Cameron

doi:10.1016/j.humpath.2021.12.013

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…Also, in keeping with the known near universal MAPK/ERK pathway activation in LCH, cyclin D1 is expressed in up to 100% of cases 26. However, this marker has low specificity, being present in many different histiocytic neoplasms, as well as in sinus histiocytes of reactive lymph nodes, albeit at low levels 27–29…”

Section: Discussionmentioning

confidence: 85%

“…26 However, this marker has low specificity, being present in many different histiocytic neoplasms, as well as in sinus histiocytes of reactive lymph nodes, albeit at low levels. [27][28][29] Considering these limitations, we assessed MUM1/ IRF4 in a group of Langerhans cell neoplasms and found that all cases of LCH, as well as 1 case of Langerhans cell sarcoma tested, were essentially negative by immunohistochemistry using an arbitrary 5% cutoff. There were 4 LCH cases with 1% to 2% cells weakly expressing MUM1/IRF4.…”

Section: Discussionmentioning

confidence: 99%

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MUM1/IRF4 is Highly Expressed in Dermatopathic Lymphadenopathy

Garcés¹,

Rudzki

Yin³

et al. 2022

American Journal of Surgical Pathology

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Dermatopathic lymphadenopathy (DL) is a distinctive type of lymph node hyperplasia that typically occurs in the setting of chronic dermatologic diseases. DL generally self-resolves following disappearance of the underlying skin stimulus and does not require any specific therapy. We recently observed multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) expression in a case of DL using immunohistochemical methods. The goal of this study was to systematically assess DL cases for MUM1/IRF4 expression and to survey other histiocytic and Langerhans cell lesions. We particularly focused on Langerhans cell histiocytosis (LCH) because the differential diagnosis of DL versus LCH in lymph nodes can be challenging. We identified high expression of MUM1/IRF4 in all 22 cases of DL tested. Specifically, MUM1/IRF4+ dendritic cells comprised 50% to 90% (median, 80%) of all dendritic cells in the paracortex of dermatopathic lymph nodes, always showing moderate or strong intensity. Among 10 DL cases stained for MUM1/IRF4 and langerin/CD207 using dual immunohistochemistry, MUM1/IRF4+ and langerin+ Langerhans cells represented 5% to 60% (median, 30%) of paracortical dendritic cells. MUM1/IRF4 was also positive in reactive Langerhans cells in skin biopsy specimens of all cases of spongiotic dermatitis (n=10) and normal skin (n=15), and was negative in all cases of LCH (n=24), Rosai-Dorfman disease (n=10), follicular dendritic cell sarcoma (n=5) and histiocytic sarcoma (n=4). In aggregate, our findings support the utility of MUM1/IRF4 to highlight the dendritic cells of DL and to distinguish DL from other histiocytic and Langerhans cells lesions.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

MUM1/IRF4 is Highly Expressed in Dermatopathic Lymphadenopathy

Garcés¹,

Rudzki

Yin³

et al. 2022

American Journal of Surgical Pathology

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“…In addition, our Western blotting analysis showed that Z HPV16E7 384 treatment did not inhibit the expression of three other cell cycle related proteins: CD147-4, CDK1, and CDK2 [ 37 , 38 ], implying that Z HPV16E7 384 specifically inhibited the expression of the cell cycle proteins cyclin D1 and CDK4 in the target cancer cells. Cyclin D1 and CDK4 are the key cell cycle regulators, which regulate the timing of the events in the cell cycle [ 39 , 40 ]. Z HPV16E7 384 treatment inhibited the expression of cyclin D1 and CDK4 to disrupt their normal cell cycle regulatory functions, leading to the cell cycle arrest at the G1/S phase in target cancer cells, which is more likely through the coordinated interactions between the cyclin D1/CDK4 and Rb/E2F1 complexes.…”

Section: Discussionmentioning

confidence: 99%

The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

et al. 2022

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Affibodies targeting intracellular proteins have a great potential to function as ideal therapeutic agents. However, little is known about how the affibodies enter target cells to interact with intracellular target proteins. We have previously developed the HPV16E7 affibody (ZHPV16E7384) for HPV16 positive cervical cancer treatment. Here, we explored the underlying mechanisms of ZHPV16E7384 and found that ZHPV16E7384 significantly inhibited the proliferation of target cells and induced a G1/S phase cell cycle arrest. Furthermore, ZHPV16E7384 treatment resulted in the upregulation of retinoblastoma protein (Rb) and downregulation of phosphorylated Rb (pRb), E2F1, cyclin D1, and CDK4 in the target cells. Moreover, treatment with dynamin or the caveolin-1 inhibitor not only significantly suppressed the internalization of ZHPV16E7384 into target cells but also reversed the regulation of cell cycle factors by ZHPV16E7384. Overall, these results indicate that ZHPV16E7384 was likely internalized specifically into target cells through dynamin- and caveolin-1 mediated endocytosis. ZHPV16E7384 induced the cell cycle arrest in the G1/S phase at least partially by interrupting HPV16E7 binding to and degrading Rb, subsequently leading to the downregulation of E2F1, cyclin D1, CDK4, and pRb, which ultimately inhibited target cell proliferation. These findings provide a rationale of using ZHPV16E7384 to conduct a clinical trial for target therapy in cervical cancer.

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“…Recent studies have shown that 1/3 of RDD cases harboring mutations in the MAPK/ERK pathway that were found to be gain-of-function mutations leading to the upregulation of p-ERK and cyclin D1/BCL-1 in the histiocytes [ 38 , 39 , 40 ]. Cyclin D1/BCL-1, a key cell-cycle regulator, represents a major downstream target of the MAPK/ERK pathway.…”

Section: Histopathology and Immunochemistrymentioning

confidence: 99%

“…Expression that is positive for Cyclin D1/BCL-1 can be associated with phosphorylated -ERK (p-ERK), reflecting the constitutive activation of MAPK pathway [ 39 ]. However, some cases show cyclin D1 upregulation and absence of p-ERK expression; hence, cyclin D1 might be regulated by other oncogenic mechanisms bypassing the ERK pathway [ 40 ]. Positive cyclin D1/BCL-1 staining in RDD is not associated with an underlying translocation of the CCND1 gene.…”

Section: Histopathology and Immunochemistrymentioning

confidence: 99%

Rosai–Dorfman Disease between Proliferation and Neoplasia

Younes

Sokol

Zhang

2022

Cancers

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Rosai–Dorfman disease (RDD) is a rare myeloproliferative disorder of histiocytes with a broad spectrum of clinical manifestations and peculiar morphologic features (accumulation of histiocytes with emperipolesis). Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms. Approximately 43% of patients presented with extranodal involvement. According to the 2016 revised histiocytosis classification, RDD belongs to the R group, including familial and sporadic form (classical nodal, extranodal, unclassified, or RDD associated with neoplasia or immune disease). Sporadic RDD is often self-limited. Most RDD needs only local therapies. Nevertheless, a small subpopulation of patients may be refractory to conventional therapy and die of the disease. Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation. In addition to typical histiocytic markers (S100/fascin/CD68/CD163, etc.), recent studies show that the histiocytes in RDD also express BCL-1 and OCT2, which might be important in pathogenesis. Additionally, the heterozygous germline mutation involving the FAS gene TNFRSF6 is identified in some RDD patients with an autoimmune lymphoproliferative syndrome type Ia. SLC29A3 germline mutation is associated with familial or Faisalabad histiocytosis and H syndrome.

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Cyclin D1 expression in Rosai-Dorfman disease: a near-constant finding that is not invariably associated with mitogen-activated protein kinase/extracellular signal–regulated kinase pathway activation

Cited by 13 publications

References 34 publications

MUM1/IRF4 is Highly Expressed in Dermatopathic Lymphadenopathy

MUM1/IRF4 is Highly Expressed in Dermatopathic Lymphadenopathy

The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

Rosai–Dorfman Disease between Proliferation and Neoplasia

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