Biological Features and Plasticity of CD56-Positive Dendritic-Like Cells: relationship to Blastic Plasmacytoid Dendritic Cell Neoplasm

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1486-1486
Author(s):  
Yohei Osaki ◽  
Akihiko Yokohama ◽  
Akio Saitoh ◽  
Kenichi Tahara ◽  
Kunio Yanagisawa ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
In Vitro Culture ◽  
Interferon Alpha ◽  
Peripheral Blood ◽  
Plasmacytoid Dendritic Cell ◽  
Mrna Levels ◽  
Gm Csf ◽  
Cell Neoplasm

Abstract Abstract 1486 Introduction: Dendritic cells (DCs) play critical roles in the induction and regulation of the innate and adaptive immune responses. Human blood DCs can be classified into plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC). In general, pDC is defined as lineage (Lin)-HLA-DR (DR)+CD123+CD11c-, and mDC is defined as Lin-DR+CD123+CD11c+. PDCs are a specific type of dendritic cells that is found in an immature form in the peripheral blood and that is the major interferon-alpha producing cell in response to viruses. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy that has a putative plasmacytoid dendritic cells origin. Unlike blood pDCs, the specific feature of BPDCN is the positive expression of CD56. In addition to these markers, BPDCNs can express various antigens, such as CD2, CD10, CD13, CD33 and even CD11c, that cause immunophenotypical diversity among cases. The goal of this study was to clarify the normal counterpart of BPDCN by analyzing the characteristics of CD56-positive blood Dendritic-like Cells (DLCs). Material and Methods: Human peripheral blood mononuclear cells (PBMNCs) were isolated by gradient centrifugation from healthy volunteers, and CD3, CD14, CD16 and CD19 antibodies were used as a lineage cocktail. We defined CD56+pDC-like cells (pDLCs) as Lin-DR+CD56+CD123+ cells, CD56+mDC-like Cells (mDLCs) as Lin-DR+CD56+CD123-CD11c+ cells, pDCs as Lin-DR+CD56-CD123+CD11c-cells and mDCs as Lin-DR+CD56-CD123+CD11c+cells. In some experiments, cells were purified from PBMNCs using a cell sorter. Sorted cells were analyzed for mRNA levels of toll-like receptors (TLRs), cytokines and transcriptional factors. Phagocytic activity and mixed lymphocyte reactions were analyzed by flow cytometry. Sorted cells were also analyzed after 4–6 days of culture with Fms-like tyrosine kinase 3 ligands (Flt3-L) and granulocyte macrophage colony-stimulating Factor (GM-CSF). Results: PBMCs comprised a small population of each cell type: 0.03% of CD56+pDLCs, 0.35% of CD56+mDLC, 0.93% of pDC 0.93%, and 0.60% of mDC. CD56+pDLCs had oval or U-shaped nuclei with condensed chromatin, and perinuclear halo, which is feature of pDC, was clearly observed in the cytoplasm. CD11c expression in CD56+pDLCs was lower than that in mDCs but higher than that in pDCs. CD56+pDLCs were not Natural Killer (NK) cells, as there was no expression of CD122 or other NK-specific antigens. Meanwhile, CD56+pDLCs had clear expression of BDCA2 and BDCA4, suggesting that this population was closely related to pDCs. Real-time quantitative (RQ) PCR assay revealed that TLRs were expressed in an intermediate level between pDCs and mDCs in CD56+pDLCs (CD56+pDLC vs. pDC vs. mDC: TLR2, 0.17 vs. 0.09 vs. 1.13; TLR4, 0.14 vs. 0.06 vs. 0.53; TLR7, 0.67 vs. 16.70 vs. 0.30; TLR9, 3.73 vs. 72.41 vs. 0.18). Expression of the transcription factors, E2-2, Irf8 and SpiB, in pDCs was higher than that in CD56+pDLCs, but lower than that in mDCs (CD56+pDLC vs. pDC vs. mDC: E2-2, 16.78 vs. 118.69 vs. 1.45; Irf8, 1.73 vs. 9.07 vs. 0.55; SpiB, 0.14 vs. 0.52 vs. 0.02). RQ−PCR after CpG stimulation revealed that CD56+pDLCs had lower interferon–alpha production when compared with pDCs (5.7405 vs. 360.881). Phagocytic capacity of CD56+pDLCs was lower than that of mDC or pDC (1.96% vs. 4.32 % vs. 52.6% for FITC-dextran positive cells in CD56+pDLCs vs. pDCs vs. mDCs). Allogeneic T cells proliferated less efficiently after culture with CD56+pDLCs than they did after culture with pDC. After in vitro culture with Flt3L and GM-CSF, the percentage of BDCA1-positive cells increased from 2.75% to 62.9%. Discussion: CD56+pDLCs were rare population in PBMNCs. Their phenotype and function were similar to pDCs, in part, but they expressed myeloid antigens and had lower function of phagocytosis and cytokine production than pDCs. In vitro culture suggested plasticity in the immunophenotype of CD56+pDLCs when compared with pDC and mDC. Collectively, these data suggest that CD56+pDLCs is a distinct new population of DCs that possesses a high degree of plasticity. These immunophenotypic characteristics and plasticity may influence the immunophenotypic diversity of BPDCNs. Disclosures: No relevant conflicts of interest to declare.

Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4591-4594 ◽  
Author(s):  
Marco Lucioni ◽  
Francesca Novara ◽  
Giacomo Fiandrino ◽  
Roberta Riboni ◽  
Daniele Fanoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Dendritic Cells ◽  
Statistical Analysis ◽  
Dendritic Cell ◽  
Clinical Presentation ◽  
Plasmacytoid Dendritic Cell ◽  
Tumor Stage ◽  
Comparative Genomic ◽  
Cell Neoplasm

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy derived from precursors of plasmacytoid dendritic cells. We analyzed 21 cases with array-based comparative genomic hybridization (aCGH). Complete or partial chromosomal losses largely outnumbered the gains, with common deleted regions involving 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) regions. CDKN2A/CDKN2B deletion was confirmed by FISH. This scenario argues for disruption of cell cycle at G1/S transition, representing a genetic landmark of BPDCN, and possibly contributing to its pathogenesis. Statistical analysis of overall survival in our series highlighted an association of poor outcome with biallelic loss of locus 9p21.3. We suggest that, in the absence of reliable parameters for predicting prognosis in BPDCN other than age, tumor stage, and/or clinical presentation, simple methods, such as FISH for CDKN2A/CDKN2B, could help to identify the most aggressive cases.

In Utero Cltc-ALK Fusion In Hematopoietic Progenitor Cells As a First Step Of Leukemogenesis In Blastic Plasmacytoid Dendritic Cell Neoplasm

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2587-2587
Author(s):  
Kiriko Tokuda ◽  
Minenori Eguchi-Ishimae ◽  
Mariko Eguchi ◽  
Eiichi Ishii
Keyword(s):  
Dendritic Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Fusion Gene ◽  
Plasmacytoid Dendritic Cell ◽  
In Utero ◽  
Guthrie Card ◽  
Myeloid Neoplasm ◽  
Cell Neoplasm ◽  
Blast Cells

Abstract Introduction Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of myeloid leukemia mainly affecting the elderly and often accompanied by cutaneous legions. It is a rare disease, and neither the genetic nor clonal origin of the disease is known. We report the first case of BPDCN with clathrin heavy chain (CLTC)-anaplastic lymphoma kinase (ALK) fusion gene. We performed a detailed analysis to understand the origin of the tumor cells and the leukemic process involved. Samples and Results Samples were collected from a female infant who was admitted under the diagnosis of hemophagocytic lymphohistiocytosis (HLH) at 1 month of age. One month later, leukemic blasts appeared in the peripheral blood showing karyotypic abnormality 46,XX,t(2;17;8)(p23;q23;p23). Fluorescence in situ hybridization with break apart probes covering the ALK gene revealed translocation of the 3’-ALK signal to der(17) and loss of the 5’ ALK signal on der(2). CLTC-ALK fusion was identified by direct sequencing of the RT-PCR product obtained from the peripheral blood specimen. Although HLH symptoms improved after one course of chemotherapy, blast cells re-appeared in the peripheral blood and bone marrow after 3 courses of chemotherapy, with a karyotype of 45, XX, t(2;17;8)(p23;q23;p23), -7. Multicolor flow cytometry showed the blast cells were weakly positive for CD4 and negative for CD3, and expression of CLTC-ALKwas confirmed in these cells. Some of the blasts were highly positive for CD123 and CD303, indicating the plasmacytoid dendritic cell phenotype and leading to the diagnosis of BPDCN. The rest of the blasts were positive for CD56 and weakly positive for CD123. Nearly half of this CD4+CD56+ population was also positive for monocytic marker, CD14. The possibility of in utero origin of the leukemic cells was tested by analyzing the presence of CLTC-ALK fusion in the Guthrie card. The genomic breakpoint of the CLTC-ALKfusion was determined by inverse PCR, and then 24 pieces of the Guthrie card containing the neonatal blood were tested for the existence of the cells carrying the same fusion breakpoint. The testing revealed the prenatal origin of the fusion gene. To explore the origin of leukemic transformation in the patient, the presence of the CLTC-ALK fusion gene was assessed in genomic DNA extracted from subpopulations sorted from the patient’s peripheral blood. As well as leukemic CD4+CD3- cells, most of the monocytes possessed the CLTC-ALK fusion gene, and a small portion of T cells, B cells and neutrophils were also positive for genomic CLTC-ALK fusion. Immature cells with high CD34 expression but without lineage markers separated from the peripheral blood were also positive for CLTC-ALKfusion. Conclusions The CLTC-ALK fusion gene was identified for the first time as the leukemia-promoting abnormality in an infant case of myeloid neoplasm BPDCN, indicating the tumorigenic potential of CLTC-ALK in myeloid progenitor cells. In addition, activated monocytes with the CLTC-ALK fusion might be responsible for the occurrence of HLH in the patient. Formation of the CLTC-ALK fusion was suggested to have occurred in a hematopoietic progenitor cells in utero, and the subsequent acquisition of monosomy 7, one of the myeloid lineage-oriented abnormalities, might have determined the cell fate to a myeloid neoplasm in this patient. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impairments of Antigen-Presenting Cells in Pulmonary Tuberculosis

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Ludmila V. Sakhno ◽  
Ekaterina Ya. Shevela ◽  
Marina A. Tikhonova ◽  
Sergey D. Nikonov ◽  
Alexandr A. Ostanin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Pulmonary Tuberculosis ◽  
Peripheral Blood ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Gm Csf ◽  
Antigen Presenting

The phenotype and functional properties of antigen-presenting cells (APC), that is, circulating monocytes and generatedin vitromacrophages and dendritic cells, were investigated in the patients with pulmonary tuberculosis (TB) differing in lymphocyte reactivity toM. tuberculosisantigens (PPD-reactive versus PPD-anergic patients). We revealed the distinct impairments in patient APC functions. For example, the monocyte dysfunctions were displayed by low CD86 and HLA-DR expression, 2-fold increase in CD14+CD16+expression, the high numbers of IL-10-producing cells, and enhanced IL-10 and IL-6 production upon LPS-stimulation. The macrophages which werein vitrogenerated from peripheral blood monocytes under GM-CSF were characterized by Th1/Th2-balance shifting (downproduction of IFN-γcoupled with upproduction of IL-10) and by reducing of allostimulatory activity in mixed lymphocyte culture. The dendritic cells (generatedin vitrofrom peripheral blood monocytes upon GM-CSF + IFN-α) were characterized by impaired maturation/activation, a lower level of IFN-γproduction in conjunction with an enhanced capacity to produce IL-10 and IL-6, and a profound reduction of allostimulatory activity. The APC dysfunctions were found to be most prominent in PPD-anergic patients. The possible role of APC impairments in reducing the antigen-specific T-cell response toM. tuberculosiswas discussed.

scholarly journals In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

Haematologica ◽  
2014 ◽  
Vol 100 (2) ◽  
pp. 223-230 ◽  
Author(s):  
F. Angelot-Delettre ◽  
A. Roggy ◽  
A. E. Frankel ◽  
B. Lamarthee ◽  
E. Seilles ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Biologic Agent ◽  
Interleukin 3 ◽  
In Vitro Sensitivity ◽  
Cell Neoplasm

scholarly journals Features of non-activation dendritic state and immune deficiency in blastic plasmacytoid dendritic cell neoplasm (BPDCN)

2019 ◽  
Vol 9 (12) ◽  
Author(s):  
Hannah C. Beird ◽  
Maliha Khan ◽  
Feng Wang ◽  
Mansour Alfayez ◽  
Tianyu Cai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cell ◽  
Peripheral Blood ◽  
Profile Analysis ◽  
Hematologic Malignancy ◽  
Plasmacytoid Dendritic Cell ◽  
Serum Samples ◽  
Molecular Features ◽  
Cell Neoplasm ◽  
Poor Outcomes

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant hematologic malignancy with poor outcomes and with just one recently approved agent (tagraxofusp). It is characterized by the abnormal proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) in its presentation within the bone marrow and peripheral blood. To identify disease-specific molecular features of BPDCN, we profiled the bone marrow, peripheral blood, and serum samples from primary patient samples using an in-house hematologic malignancy panel (“T300” panel), transcriptome microarray, and serum multiplex immunoassays. TET2 mutations (5/8, 63%) were the most prevalent in our cohort. Using the transcriptome microarray, genes specific to pDCs (LAMP5, CCDC50) were more highly expressed in BPDCN than in AML specimens. Finally, the serum cytokine profile analysis showed significantly elevated levels of eosinophil chemoattractants eotaxin and RANTES in BPDCN as compared with AML. Along with the high levels of PTPRS and dendritic nature of the tumor cells, these findings suggest a possible pre-inflammatory context of this disease, in which BPDCN features nonactivated pDCs.

The Induction of Dendritic Cells with IFN-alpha and GM-CSF from Bone Marrow Mononuclear Cells from Patients with Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4873-4873
Author(s):  
Shuier Zhen ◽  
Jie Jin ◽  
Xiangmin Tong
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Bone Marrow Mononuclear Cells ◽  
Gm Csf

Abstract Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell with the typical Philadelphia (Ph) chromosome cytogenetic abnormality. IFN-a has been proven to be effective for patients in the chronic phase of myelogenous leukemia (CML), yet the mechanisms of the antitumor action of these cytokines are still a matter of debate. Dendritc cells (DCs) are potent antigen-presenting cells that prime effective T-cell response aginst tumour antigens. Recent studies have shown that IFN-a can exert a variety of effects on dendritic cells (DCs), which may play an important role in the induction of an antitumor immunity. Human DCs can be generated in vitro from peripheral blood(PB) monocytes or from CD34+ haematopoietic precursor cells in culture medium containing human granulocyte macrophage-colony stimulating factor (GM-CSF), IL-4 and some other cytokines. Previous studies have shown a new effective protocol for the generation of human DCs from unseparated BM aspirate cells with excellent functional capacity of antigen uptake and of stimulating naive and memory T cell responses superior to that of DCs from peripheral blood(PB) monocytes. We, therefore, explored whether treatment with IFN-a may influence the CML bone marrow mononuclear cells(BMMNCs) derived DCs in vitro. Treatment BMMNCs of 12 patients with CML in chronic phase with IFN-a+rhGM-CSF(IFN-a-DC) generated DCs with more mature phenotype properties expressing higher of CD80,CD86,HLA-DR,CD83 compared to the CML- BMMNCs treated with rhGM-CSF+IL-4(IL-4-DC). And in parallel with phenotypes, IFN-a-DC also showed more effective than IL-4-DC in eliciting an allogeneic mixed lymphocyte reaction by MTT assay. FISH confirmed the DCs of both groups were leukemic origin. These findings demonstrate that IFN-a promotes the differentiation/maturation of DCs derived from BMMNCs of patients with CML in vitro, these studies also broaden the clinical scope of IFN-a as a promising agent in the immunotherapy of CML.

Blastic Plasmacytoid Dendritic Cell Neoplasm: Report of Three Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4703-4703
Author(s):  
Paola Carluccio ◽  
Mario Delia ◽  
Anna Mestice ◽  
Domenico Pastore ◽  
Alessandra Ricco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Disease Progression ◽  
Plasmacytoid Dendritic Cell ◽  
Skin Lesions ◽  
World Health ◽  
Cell Neoplasm ◽  
Blast Cells

Abstract Abstract 4703 The World Health Organization (WHO) recently published a revised, updated edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues, including new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities – some defined mainly by genetic and immunophenotypic features – that have only recently been characterized. Particularly, the diagnosis and classification of acute leukemias of ambiguous lineage is debated; among these: “blastic NK-cell lymphoma” and “agranular CD4+/CD56+ hematodermic neoplasms”. Both of them are now known to be, in virtually all cases, a tumor derived from precursors of a specialized subset of dendritic cells, plasmacytoid dendritic cells, and so are myeloid-related neoplasms defined as blastic plasmacytoid dendritic cell neoplasm (BPDCN). This is a clinically aggressive neoplasm that is usually characterized at onset by solitary or multiple skin lesions, often with associated regional lymphadenopathy, and frequently by involvement of the PB and BM. Leukemic cells show submembranous cytoplasmic vacuoles and pseudopodia-like extensions of agranular cytoplasm. The blasts in such cases do not express myeloperoxidase or nonspecific esterase, and are characterized by the expression of CD4, CD43, CD56, CD123, BDCA-2/CD303, TCL1, and CLA; CD7 and CD33 are not uncommonly expressed as well, and TdT is expressed in about 30% of cases. There is no expression of CD34 or CD117. Here we report three cases with clinical data, cytological and immunophenotypic findings strongly suggesting the diagnosis of BPDCN. Case 1 An 80 year-old-man was admitted to our institution on December 2006. He referred the occurrence of skin lesions since January 2005, when a diagnosis of extranodal B-cell non-Hodgkin lymphoma was made and treatment with conventional chemotherapy was performed, but without achieving any response. At our evaluation he presented leukocytosis (144 × 109/L) associated with purplish, firm nodules on the trunk, arms and face. Peripheral blood and bone marrow aspirate showed the presence of blast cells with a lymphoid appearance, granular periodic acid-Schiff (PAS) positivity and a high expression of CD33, CD4, and CD56. He was treated with AML-like therapy, but died of disease progression. Case 2 A 79-year old woman was admitted in December 2006 with a 2-month history of anemia, splenomegaly, and weight loss of 10 kg in the last year. Laboratory tests were as follows: Hb, 41 g/L; leukocytes, 2.5 × 109/L (with 10% of blast cells); platelets, 43 × 109/L. No lymphadenopathy or skin lesions were present. Bone marrow examination revealed 41% of small to medium-sized blast cells without Auer rods or granula and negative reactivity to myeloperoxidase, esterase and PAS. She was treated with an AML-like protocol; she achieved partial response, but died after three months, of disease progression. Case 3 A 69-year-old man was admitted to our Institution for cytopenia in June 2009. He referred the occurrence of brownish-purple firm nodules on the trunk since April 2009. At our evaluation he presented pancytopenia; bone marrow aspiration was performed and revealed infiltration by 65% of blasts with reticulated chromatin, evident nucleoli, a vacuolated cytoplasm and pseudopodia-like expansions. The blasts were negative for myeloperoxidase, monocyte esterase and PAS staining. Skin biopsy revealed a dermal infiltration by the same blastic-cell BM population. He underwent AML-like therapy and, although the skin lesions disappeared, 30% blastic bone marrow infiltration persisted. Morphological revision of these cases, selected for their peculiar immunophenotype reported in the following Table, revealed the same cytological features and cytochemical reactivity in cases 2 and 3; case 1 had a lymphoblastic-like morphology and showed PAS positivity, but the lack of cCD3 was not consistent with the diagnosis of ALL. All the cases were FLT3-ITD+. We suggest that a correct modern panel of MoAb with a careful morphological examination could help to pose the diagnosis of BPDCN, which typically affects older patients and is characterized by poor prognosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD22 expression on blastic plasmacytoid dendritic cell neoplasms and reactivity of anti-CD22 antibodies to peripheral blood dendritic cells

2009 ◽  
Vol 76B (4) ◽  
pp. 237-248 ◽  
Author(s):  
Edmunds Z. Reineks ◽  
Ebenezer S Osei ◽  
Arlene Rosenberg ◽  
Jeffrey Auletta ◽  
Howard J. Meyerson
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Peripheral Blood ◽  
Plasmacytoid Dendritic Cell
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