Intracytoplasmic detection of TCL1—but not ILT7—by flow cytometry is useful for blastic plasmacytoid dendritic cell leukemia diagnosis

Angelot‐Delettre, Fanny; Biichlé, Sabéha; Ferrand, Christophe; Seillès, Estelle; Gaugler, Béatrice; Harrivel, Véronique; Rosenthal-Allieri, Maria Alessandra; Deconinck, Eric; Saas, Philippe; Garnache‐Ottou, Francine

doi:10.1002/cyto.a.22072

Cited by 20 publications

(25 citation statements)

References 24 publications

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“…Moreover the viability of these two BPDCN cell lines decreased in a dose-dependent manner ( Figure 1B). Similarly, after treatment with SL-401 at the experimental dose of 365 pM (21 ng/mL), the viability of 12 samples of freshly isolated BPDCN primary cells decreased significantly from 50 ± 4% (range, 31-71) to 10 ± 1% (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. As expected, the CD123 neg (Daudi) cells were not sensitive to treatment with SL-401 concentrations as high as 365 pM for 18 h [viability was unchanged from 65% (range, 88-41) to 61% (range, 83-41) in cells untreated or treated with SL-401, respectively, n=3; Figure 1A,B].…”

Section: Sl-401 Is Cytotoxic Against Blastic Plasmacytoid Dendritic Cmentioning

confidence: 98%

“…In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent Fanny Angelot-Delettre, [1][2][3][4] Bernard Royer, [1][2][3][4]6 Eric Deconinck, [1][2][3][4]6 Eric K. Rowinsky, 7 Christopher Brooks, 7 Valerie Bardet, 8 Blandine Benet, 9 Hind Bennani, 10 Zehaira Benseddik, 11 Agathe Debliquis, 12 Daniel Lusina, 13 Mikael Roussel, 14 Françoise Solly, 15 Michel Ticchioni, 16 Philippe Saas, [1][2][3][4]17 and Francine Garnache-Ottou…”

confidence: 99%

“…5,6 Malignant cells isolated from skin, lymph nodes, bone marrow, spleen and/or other tissues usually express the following markers: interleukin-3 receptor alpha (IL-3Ra or CD123), BDCA2 (CD303), BDCA4 (CD304), TCL1 and ILT7. [7][8][9] Currently, there is no consensus regarding the optimal treatment modality for BPDCN. Several treatments, including multi-agent chemotherapy regimens, symptomatic approaches (e.g.…”

Section: Introductionmentioning

confidence: 99%

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

Angelot‐Delettre¹,

Roggy²,

Frankel³

et al. 2014

Haematologica

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ABSTRACTlabile group of amino acids to a diphtheria toxin (DT) payload that has been truncated at its receptor binding region. 20 Since IL-3, the natural ligand for IL-3R, binds with very high specificity and avidity, 21 SL-401 is able to transport DT efficiently and preferentially to cells that overexpress IL-3R, leading to internalization followed by receptor-mediated endocytosis and localization of SL-401 to early endosomes. After cleavage of the SL-401 DT constituent in the acidic medium of endosomes, DT translocates into the cytosol and binds to ADP-ribosylated elongation factor 2, leading to blockade of protein synthesis and cell death. 22 Given the ubiquitous and high expression of IL-3R by BPDCN and the lack of therapies available to treat BPDCN, SL-401 is a potential therapeutic for BPDCN. The present study evaluated the cytotoxicity of SL-401 against patient-derived BPDCN cell lines (CAL-1 and GEN2.2) and primary BPDCN cells isolated directly from 12 patients. The investigations were performed in vitro, as well as in vivo in a murine model of BPDCN. The aim of the study was to provide further support for the use of SL-401 in patients suffering from BPDCN. Methods Patients' cells and cell linesPeripheral blood or bone marrow cells were obtained for diagnostic purposes from 12 BPDCN patients (Table 1) from our national network that collects data and cells from cases diagnosed in France since (authorization number #DC-2008. BPDCN was diagnosed from the results of histopathology and immunostaining of cutaneous lesions, blood or bone marrow. 2,8 Two established cell lines derived from BPDCN patients were used (GEN 2.2, patent #0215927, Dr. Plumas, EFS Rhone-Alpes, Grenoble, France and CAL-1, Dr. Maeda, Nagasaki University, Japan) as well as TF/H-Ras (Prof. Frankel) and CD123 neg (MFI<800) Daudi cell lines (ACC78, DSMZ Braunschweig, Germany) as positive and negative controls, respectively. Other lymphoid and myeloid leukemic cells used to compare sensitivity to SL-401 are described in the Online Supplementary Appendix. Drug and cultureThe SL-401 drug (Stemline Therapeutics, New York, NY, USA) was stored at -80°C and tested at eight concentrations ranging from 365 pM to 0.08 fM (21 ng/mL to 0.4 ng/mL) in order to cover (including myeloperoxidase, CD13, CD33, CD117, CD15, CD65, CD14, CD64); T : T lymphoid markers (including membrane CD3, intracytoplasmic CD3, CD7, CD5, CD2, CD8) Cytotoxicity evaluation by flow cytometryFlow cytometry was performed using a CANTO II cytometer (BD Biosciences, San Jose, CA, USA) and DIVA 6.2 software (BD Biosciences). The cytotoxic effects of SL-401 and the various drugs were evaluated using annexin-V and 7-amino actinomycin D (AV/7AAD) and a panel of different monoclonal antibodies to gate the blastic population described in the Online Supplementary Appendix. In the mouse model, anti-mouse and anti-human CD45 plus anti-human CD123, CD4, CD56, CD304 were used to identify BPDCN human cells (Online Supplementary Appendix). A defined number of calibrated 3-mm latex beads (Flowco...

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Section: Sl-401 Is Cytotoxic Against Blastic Plasmacytoid Dendritic Cmentioning

confidence: 98%

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Angelot‐Delettre¹,

Roggy²,

Frankel³

et al. 2014

Haematologica

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“…BPDCN was diagnosed based on histopathology and immunostaining of cutaneous lesions, blood, or bone marrow samples, as described. [26][27][28] This study was approved by our local ethics committee (Comité de Protection des Personnes [CPP] Est II, Besançon, France).…”

Section: Bpdcn Collectionmentioning

confidence: 99%

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Ceroi

Masson

Roggy

et al. 2016

Blood

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Key Points• LXR activation inhibits BPDCN cell survival through the increase of cholesterol efflux, the inhibition of NF-kB, and IL-3 signaling.• Treatment with LXR agonists can be proposed as a new therapeutic approach for BPDCN.Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. (Blood. 2016;128(23):2694-2707

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“…L'aspect initial cytologique est celui d'un lymphome T pléomorphe à grandes cellules mais devant la négativité des marqueurs CD20 et CD3, il faut savoir rechercher les marqueurs CD4 et CD56. Le recherche du proto-oncogène TCL1 (T-cell leukaemia/lymphoma) permet également de confirmer le diagnostic, ainsi que les marqueurs BDCA-2 (blood dendritic cell antigen) et CD2AP (CD2-associated protein), marqueurs des cellules dendritiques [18]. Il existe des anomalies cytogénéti-ques dans plus de deux tiers des cas, comme une délétion 5q.…”

Section: Discussionunclassified

Manifestations cutanées révélatrices d’une leucémie aiguë dendritique plasmocytoïde (LADP) : deux observations

et al. 2015

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Intracytoplasmic detection of TCL1—but not ILT7—by flow cytometry is useful for blastic plasmacytoid dendritic cell leukemia diagnosis

Cited by 20 publications

References 24 publications

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

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

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Manifestations cutanées révélatrices d’une leucémie aiguë dendritique plasmocytoïde (LADP) : deux observations

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