Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm

Menezes, Juliane; Acquadro, Francesco; Wiseman, Michele S.; Gómez‐López, Gonzalo; Salgado, Rocío; Talavera-Casañas, J G; Buño, Ismael; Cervera, José; Montes‐Moreno, Santiago; Hernández-Rivas, Jesús M.; Ayala, Rosa; Calasanz, Marı́a José; Larráyoz, María José; Brichs, L F; González-Vicent, Marta; Pisano, David G.; Piris, Miguel Á.; Álvarez, Sara; Cigudosa, Juan C.

doi:10.1038/leu.2013.283

Cited by 148 publications

(132 citation statements)

References 43 publications

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“…In the present study, the karyotype examinations of the bone marrow were normal in both patients; however, karyotype examinations of biopsy specimens were not performed. In addition, previous studies reported gene abnormalities, including deletions, such as CDKN1B, CDKN2A-ARF-CDKN2B (31), increased expression, such as HES6, FLT3 and RUNX2 (32), and mutations, such as TET2 and ASXL1 (33); however, to the best of our knowledge, no fusion genes were previously reported. In the present study, leukemia-related fusion gene detection was performed for both patients due to the bone marrow involvement; the results were MLL/ENL-positive (only in case 2) and, to the best of our knowledge, this is the first reported pediatric BPDCN case with a positive result for MLL/ENL.…”

Section: Discussionmentioning

confidence: 47%

Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases

Deng

Yang

Kuang

et al. 2017

Molecular and Clinical Oncology

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Abstract. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a newly characterized, rare malignant tumor of the skin and hematopoietic system. BPDCN occurs mainly in the elderly, whereas it is rarer among children, and has variable clinical manifestations. Optimal chemotherapeutic regimens for the treatment of BPDCN have not yet been determined and this tumor has a poor prognosis. In this study, two pediatric cases of BPDCN, including a 7-year-old female and a 9-year-old male patient, diagnosed at the Xiangya Hospital of Central South University over the past 2 years, were retrospectively reviewed. Both cases exhibited multiple organ involvement, although the clinical manifestations differed; they were diagnosed with BPDCN based on the clinical manifestations, pathological and immunohistochemical findings, which included positivity for CD4, CD56 and CD123. A high-risk acute lymphocytic leukemia (ALL) chemotherapy regimen was administered to both patients. The patient in the first case achieved a complete remission, but unfortunately her parents refused follow-up treatment and she succumbed to the disease 9 months after the initial diagnosis. The second patient was treated for a total of three courses with a chemotherapy regimen including daunorubicin, cytarabine and etoposide, followed by two courses of the high-risk ALL chemotherapy regimen; unfortunately, a remission was not achieved and the patient was scheduled to receive hematopoietic stem cell transplantation. Thus, not all pediatric BPDCN patients may be able to achieve complete remission following chemotherapy with the high-risk ALL regimen, and other treatment options must be investigated in the future.

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Section: Discussionmentioning

confidence: 47%

Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases

Deng

Yang

Kuang

et al. 2017

Molecular and Clinical Oncology

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“…Overall, immune-based therapy using SL-401 appears to be an appropriate way to treat BPDCN patients. New approaches based on immunomodulators 41 or demethylating agents 40 must be further evaluated and compared − or associated − with SL-401.…”

Section: Discussionmentioning

confidence: 99%

“…13 Thus, targeted or immune-based therapies are alternative strategies to treat this aggressive leukemia. [39][40][41] Here, we propose that SL-401 is an efficient target-based therapy available for clinical trials and has already been shown to have favorable effects in patients with refractory or relapsed AML or myelodysplastic syndrome, although expression of CD123 is lower on myeloid blasts than on BPDCN cells. 23 We recently published data from a phase I/II clinical study involving 11 BPDCN patients.…”

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confidence: 99%

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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“…Diagnosis relies on strict immunophenotypic criteria by immunochemistry (IHC) and/or flow cytometry (FCM) [1][2][3][4][5][6]. The minimum requirement for diagnosis is a CD41, CD561, and CD1231 phenotype associated with negativity for lineage specific (Lin 2 ) markers; the diagnosis is further supported by expression of BDCA2/CD303 and other plasmacytoid dendritic cell-associated antigens (e.g., TCL1 and CD2AP).…”

Section: Introductionmentioning

confidence: 99%

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10‐Color flow cytometry diagnosis and HyperCVAD therapy

Deotare

Yee

et al. 2016

American J Hematol

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Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four‐tube 10‐color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA‐DR, CD71. Seven patients received front‐line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo‐HCT). For a median follow up of 13.3 months, the 1‐year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10‐color FCM using a four‐tube AL panel demonstrating a characteristic pattern of antigen expression. Front‐line induction chemotherapy with HyperCVAD can yield high remission rates, but allo‐HCT is required for long‐term durable remissions. Am. J. Hematol. 91:283–286, 2016. © 2015 Wiley Periodicals, Inc.

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Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm

Cited by 148 publications

References 43 publications

Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases

Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases

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

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10‐Color flow cytometry diagnosis and HyperCVAD therapy

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