The Experts below are selected from a list of 9894 Experts worldwide ranked by ideXlab platform
Andrew A Lane - One of the best experts on this subject based on the ideXlab platform.
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case 47 blastic Plasmacytoid Dendritic Cell neoplasm presenting with deep purple nodules
2021Co-Authors: A N Bui, Andrew A Lane, N R LeboeufAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy primarily in elderly males. Almost all patients present with cutaneous tumors characterized by purpuric hue secondary to thrombocytopenia. Lymphadenopathy and pancytopenia are noted to have varying degrees, and CNS involvement is seen in up to 30% of cases. BPDCN arises from Plasmacytoid Dendritic Cells. Those are large Cells typically positive for CD4, CD56, BDCA-2, CD123, and TCL1 and negative for markers of myeloid, T-lymphoid, B-lymphoid, or monocyte lineage. Up to 10–20% of patients with BPDCN have a concurrent history of hematologic malignancy, including myelodysplastic syndrome, chronic myelomonocytic leukemia, and acute myeloid leukemia. BPDCN often undergoes a leukemic transformation with a median survival of less than 1 year. A new subset of skin-limited BPDCN with an exCellent prognosis was recently defined; however, it is not clear which patient will remain to have a skin-limited disease since cases of metastatic spread after a presentation with an isolated cutaneous nodule were also described.
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novel therapies for blastic Plasmacytoid Dendritic Cell neoplasm
Hematology-oncology Clinics of North America, 2020Co-Authors: Andrew A LaneAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is an orphan hematologic malignancy with poor outcomes. Tagraxofusp (SL-401) was the first drug approved specifically for patients with BPDCN, in 2018. Additional therapeutic strategies are still needed to improve survival and minimize treatment-related toxicity. This article outlines novel targeted approaches that are in preclinical or clinical development for BPDCN. Although there is no known targetable genetic abnormality that defines BPDCN, data from functional testing of primary tumors, gene expression analyses, and adaptation of targeted drug approaches from other cancers to BPDCNs harboring specific mutations have nominated several promising strategies.
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evidence for separate transformation to acute myeloid leukemia and blastic Plasmacytoid Dendritic Cell neoplasm from a shared ancestral hematopoietic clone
Leukemia & Lymphoma, 2020Co-Authors: Marlise R Luskin, Annette S Kim, Sanjay S Patel, Kyle Wright, Nicole R Leboeuf, Andrew A LaneAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare hematologic neoplasm of presumed Dendritic Cell origin. BPDCN typically affects older men with cutaneous and often extracutaneous – ma...
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tagraxofusp the first cd123 targeted therapy and first targeted treatment for blastic Plasmacytoid Dendritic Cell neoplasm
Expert Review of Clinical Pharmacology, 2019Co-Authors: Minas P Economides, Andrew A Lane, Deborah Mccue, Naveen PemmarajuAbstract:Introduction: CD123 or interleukin 3 receptor alpha is overexpressed in multiple hematologic malignancies. Tagraxofusp is an intravenously administered CD123-directed cytotoxin consisting of the fusion of interleukin-3 with a truncated diphtheria toxin payload and was recently approved by the Food and Drug Administration for the treatment of adults and children aged 2 and older with blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN). Areas Covered: In this review, we discuss the use of tagraxofusp in BPDCN, and active clinical trials involving this agent in several hematologic malignancies are also presented. Tagraxofusp has significant efficacy in patients with BPDCN and manageable safety profile, with the most commonly reported adverse events being asymptomatic elevation of alanine and aspartate aminotransferase levels, hypoalbuminemia, peripheral edema, and thrombocytopenia. The most serious side effect is capillary leak syndrome that can be lethal in some cases but the risk may be mitigated by early recognition and intervention. Expert Opinion: Tagraxofusp has been introduced as a novel treatment of BPDCN, a rare hematologic malignancy, for which no standard therapy previously existed. Many patients treated with this agent were able to be bridged to stem Cell transplantation, including older patients. In the future, combinations of tagraxofusp with other targeted agents will be explored.
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blastic Plasmacytoid Dendritic Cell neoplasm current insights
Clinical Lymphoma Myeloma & Leukemia, 2019Co-Authors: Sangeetha Venugopal, Andrew A Lane, Selena Zhou, Siraj El M Jamal, John MascarenhasAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare clonal hematologic malignancy of Plasmacytoid Dendritic Cell precursors. The presentation and clinical course of BPDCN is widely heterogeneous and was most recently categorized as a distinct clinical entity by the World Health Organization in 2016. The expanded understanding of the pathobiology of BPDCN has improved diagnostic accuracy and informed novel targeted therapeutic options. The United States Food and Drug Administration-approval of tagraxofusp (SL-401) in December 2018 has focused attention on this leukemia frequently associated with skin involvement. Herein, we aim to: (1) review etiology; (2) summarize diagnostic criteria; and (3) discuss historic treatments and novel therapies for BPDCN.
Naveen Pemmaraju - One of the best experts on this subject based on the ideXlab platform.
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tagraxofusp the first cd123 targeted therapy and first targeted treatment for blastic Plasmacytoid Dendritic Cell neoplasm
Expert Review of Clinical Pharmacology, 2019Co-Authors: Minas P Economides, Andrew A Lane, Deborah Mccue, Naveen PemmarajuAbstract:Introduction: CD123 or interleukin 3 receptor alpha is overexpressed in multiple hematologic malignancies. Tagraxofusp is an intravenously administered CD123-directed cytotoxin consisting of the fusion of interleukin-3 with a truncated diphtheria toxin payload and was recently approved by the Food and Drug Administration for the treatment of adults and children aged 2 and older with blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN). Areas Covered: In this review, we discuss the use of tagraxofusp in BPDCN, and active clinical trials involving this agent in several hematologic malignancies are also presented. Tagraxofusp has significant efficacy in patients with BPDCN and manageable safety profile, with the most commonly reported adverse events being asymptomatic elevation of alanine and aspartate aminotransferase levels, hypoalbuminemia, peripheral edema, and thrombocytopenia. The most serious side effect is capillary leak syndrome that can be lethal in some cases but the risk may be mitigated by early recognition and intervention. Expert Opinion: Tagraxofusp has been introduced as a novel treatment of BPDCN, a rare hematologic malignancy, for which no standard therapy previously existed. Many patients treated with this agent were able to be bridged to stem Cell transplantation, including older patients. In the future, combinations of tagraxofusp with other targeted agents will be explored.
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tagraxofusp in blastic Plasmacytoid Dendritic Cell neoplasm
The New England Journal of Medicine, 2019Co-Authors: Naveen Pemmaraju, Andrew A Lane, Kendra L Sweet, Anthony S Stein, Sumithira Vasu, William Blum, David A Rizzieri, Eunice S Wang, Madeleine Duvic, Mark J SloanAbstract:Abstract Background Blastic Plasmacytoid Dendritic-Cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed Plasmacytoid Dendritic Cells that overexpress interleukin-...
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blastic Plasmacytoid Dendritic Cell neoplasm bpdcn on social media bpdcn increasing exposure over two years since inception of a disease specific twitter community
Current Hematologic Malignancy Reports, 2018Co-Authors: Naveen Pemmaraju, Audun Utengen, Vikas Gupta, Michael A Thompson, Andrew A LaneAbstract:Engagement on social media for professional, healthcare-related communication is rapidly rising around the world. We aimed to better understand the dynamics of a rare disease Twitter hashtag community. Twitter has served as a platform for academic discussion, a method for knowledge dissemination directly from medical meetings, and a venue for patient caregiver and support groups. One example of a rare cancer that has seen an increase in available information via Twitter is blastic Plasmacytoid Dendritic Cell neoplasm, or BPDCN. This field has recently experienced a new wave of interest from various healthcare stakeholders in light of key new scientific breakthroughs and novel clinical trials now starting to be available. In order to bring all relevant healthcare stakeholders together, the investigators of this article created a disease-specific Twitter community: #BPDCN = “blastic Plasmacytoid Dendritic Cell neoplasm on social media” which has led to higher levels of engagement and discussion in the field. This article focuses on our analysis of advanced Twitter user-metrics in the second year of #BPDCN and discusses future directions for this rare cancer online disease community.
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analysis of first year twitter metrics of a rare disease community for blastic Plasmacytoid Dendritic Cell neoplasm bpdcn on social media bpdcn
Current Hematologic Malignancy Reports, 2017Co-Authors: Naveen Pemmaraju, Audun Utengen, Vikas Gupta, Michael A Thompson, Andrew A LaneAbstract:The use of Twitter, one of the most commonly engaged social media platforms in the world, is increasing among the general public. Notably, this trend has also been observed among those involved in the healthcare field. With its ability to readily connect diverse groups of stakeholders in a given area of interest, Twitter has become a focal point for those involved in increasing awareness and information exchange in orphan disease fields. Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with generally poor long-term outcomes for adult patients and no standard therapeutic guidelines. Coupled with its low incidence rate, the disease has experienced a number of name changes over the past three decades (e.g., blastic NK Cell lymphoma, CD4+CD56+ hematodermic tumor), thereby historically resulting in difficulties in its clinico-pathologic diagnosis and treatment approaches. All of these factors have led to a striking gap in terms of accurate information available to patients and the general public. Therefore, there is an urgent need for the development of more venues for the dissemination of information, particularly online, for this rare cancer. In this context, we began the Twitter medical community, #BPDCN, over a year ago, to help fill this information void. Now, completing its first year of existence, we aimed to analyze the metrics of Twitter use in order to better understand and to describe the characteristics and reach in of #BPDCN, and to determine the feasibility of starting and maintaining a disease-specific hashtag community in a particularly rare cancer.
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social media and internet resources for patients with blastic Plasmacytoid Dendritic Cell neoplasm bpdcn
Current Hematologic Malignancy Reports, 2016Co-Authors: Naveen Pemmaraju, Vikas Gupta, Michael A Thompson, Andrew A LaneAbstract:The incorporation of Internet resources and the use of social media among patients, clinicians, advocates, and researchers in the field of hematology and oncology are growing in importance. Utilization of online information sharing is rising, especially among those involved in rare blood cancer fields, which have generally featured a paucity of reliable, updated information. In particular, blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN), an uncommon, but highly aggressive hematologic malignancy, is one example of a cancer with limited information readily available to the general public. The infrequent incidence of BPDCN, the challenges in recognizing the disease and making a clinico-pathologic diagnosis, and the lack of standard therapies are some of the reasons accounting for the dearth of expert opinion, scientific publications and discussion, and accessibility of online information for patients. This article highlights social media and Internet sources available for patients and other healthcare stakeholders in the field of BPDCN and discusses our efforts to increase awareness and propagation of BPDCN electronic resources, including the founding of an online Twitter community, #BPDCN.
Mohamed E Salama - One of the best experts on this subject based on the ideXlab platform.
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optimized immunohistochemical panel to differentiate myeloid sarcoma from blastic Plasmacytoid Dendritic Cell neoplasm
Modern Pathology, 2014Co-Authors: Nikhil A Sangle, Robert L Schmidt, Jay L Patel, Archana M Agarwal, Jeffrey L Medeiros, Sherrie L. Perkins, Mohamed E SalamaAbstract:Optimized immunohistochemical panel to differentiate myeloid sarcoma from blastic Plasmacytoid Dendritic Cell neoplasm
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optimized immunohistochemical panel to differentiate myeloid sarcoma from blastic Plasmacytoid Dendritic Cell neoplasm
Modern Pathology, 2014Co-Authors: Nikhil A Sangle, Robert L Schmidt, Archana M Agarwal, Jeffrey L Medeiros, Sherrie L. Perkins, Jay Patel, Mohamed E SalamaAbstract:Myeloid sarcoma (MS) and blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) can be difficult to distinguish morphologically, even with the use of extensive immunohistochemical studies. Three new research markers, myxovirus A (MxA), CLA/CD162, and CD303/BDCA-2, have been reported to be positive in BPDCN, but their clinical utility has never been tested. We compared these markers to other antibodies that have been used traditionally to distinguish MS from BPDCN to assess the utility of these newer antibodies in differential diagnosis. Formalin-fixed, paraffin-embedded tissue sections of 23 MS and 17 BPDCN cases were assessed using immunohistochemical analysis for CD4, CD14, CD33, CD43, CD56, CD68, CD123, CD163, myeloperoxidase, lysozyme, terminal deoxynucleotidyl transferase (TdT), T-Cell leukemia 1 (TCL-1), MxA, cutaneous lymphocyte-associated antigen (CLA)/CD162, and blood Dendritic Cell antigen 2 (BDCA2)/CD303. We identified antibodies with a high predictive value of ≥ 90% and used these markers to develop an approach to classification using specific staining criteria. Diagnostic classification criteria were based on staining patterns of one or more of the seven markers. BPDCN was associated with positive staining for CD56, TdT, or TCL1, or negative staining for lysozyme. MS was associated with positive staining for lysozyme or myeloperoxidase, or negative staining for CD56, CD123, myxovirus, or TCL1. The immunohistochemical staining patterns observed using a panel that includes MPO, CD56, CD123, TCL1, TdT, and MxA, are predictive of MS or BPDCN. In this study, neither CD162 nor CD303 had good predictive value in distinguishing MS from BPDCN.
Vinitha Mary Kuruvilla - One of the best experts on this subject based on the ideXlab platform.
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abstract 2560 preclinical efficacy of allogeneic anti cd123 car t Cells for the therapy of blastic Plasmacytoid Dendritic Cell neoplasm bpdcn
Cancer Research, 2018Co-Authors: Kathryn L Black, Sergej Konoplev, Ammar S Naqvi, Roman Galetto, Agnes Gouble, Julianne Smith, Antonio Cavazos, Qi Zhang, Vinitha Mary Kuruvilla, Sattva S NeelapuAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with historically poor outcomes and no established standard of care. Nearly 100% of patients with BPDCN overexpress CD123, and targeting CD123 emerged as an attractive therapeutic target given its differential expression on BPDCN Cell surface. UCART123 product (Cellectis) uses genetically modified allogeneic T-Cells (derived from healthy donors, so-called “off the shelf”) containing an anti-CD123 CAR and a RQR8 depletion ligand that confers susceptibility to rituximab. The expression of the T-Cell receptor (TCR) is abrogated through the inactivation of the TCRα constant gene, using Cellectis9 TALEN® gene-editing technology. We have previously reported the selective in vitro anti-tumor activity of UCART123 Cells against CD123+ primary BPDCN samples using cytotoxicity assays, T-Cell degranulation assay and the secretion of IFNγ and other cytokines (IL2, IL5, IL6, IL-13 and TNF-α) by UCART123 Cells when cultured in the presence of BPDCN Cells (Tianyu Cai, 2017 ASH). However, UCART123 had minimum toxicity against normal bone marrow Cells. To evaluate in vivo anti-tumor activity of UCART123 Cells, we established two patient-derived xenografts (PDX1-2) from patients with relapsed BPDCN in NSG-SGM3 mice. In PDX-1 model, all mice in vehicle-treated group died by D53, with high tumor burden in peripheral blood, spleen and bone marrow. Three out of 9 (33%) mice treated with 3×106 UCART123 and Six out of 9 (67%) mice treated with 10×106 UCART123 were alive and disease-free at the end of the study (D299). In PDX-2 model, while UCART123 similarly extended survival of the mice (D104-241), relapses occurred in all treatment cohorts at D90-155. Flow cytometric analysis showed that all of the relapses were associated with emergence of CD123- BPDCN clones (95-96% CD123-). To understand the molecular basis for loss of CD123 surface expression, we isolated RNA from two CD123 positive samples from vehicle group and two CD123 negative samples from 1×106 UCART123 group. RT-PCR and RNA-seq detected the presence of full-length transcripts containing exons 1-12 in both CD123 positive samples. In one of the two CD123 (-) samples, CD123 transcripts were completely absent, along with loss of transcripts of neighboring genes. In another CD123 (-) sample, CD123 transcripts containing only exons 1-9 were detected, indicating the presence of a truncation. Interestingly, if translated, this transcript would produce a protein isoform lacking the transmembrane domain (Ex 10). In summary, UCART123 therapy results in BPDCN eradication and long-term disease-free survival in a subset of primary BPDCN PDX models. However, loss of CD123 through diverse genetic mechanisms could lead to escape from UCART123 therapy and cause relapses. A phase I trial of UCART123 in BPDCN is opened for enrollment (NCT03203369). Citation Format: Tianyu Cai, Kathryn L. Black, Ammar Naqvi, Roman Galetto, Agnes Gouble, Julianne Smith, Antonio Cavazos, Lina Han, Qi Zhang, Vinitha Kuruvilla, Sergej Naumovich Sergej Konoplev, Sattva S. Neelapu, Andrew A. Lane, Monica L. Guzman, Hagop Kantarjian, Andrei Thomas-Tikhonenko, Naveen Pemmaraju, Marina Konopleva. Preclinical efficacy of allogeneic anti-CD123 CAR T-Cells for the therapy of blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2560.
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abstract 2560 preclinical efficacy of allogeneic anti cd123 car t Cells for the therapy of blastic Plasmacytoid Dendritic Cell neoplasm bpdcn
Cancer Research, 2018Co-Authors: Tianyu Cai, Kathryn L Black, Ammar S Naqvi, Roman Galetto, Agnes Gouble, Julianne Smith, Antonio Cavazos, Qi Zhang, Lina Han, Vinitha Mary KuruvillaAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with historically poor outcomes and no established standard of care. Nearly 100% of patients with BPDCN overexpress CD123, and targeting CD123 emerged as an attractive therapeutic target given its differential expression on BPDCN Cell surface. UCART123 product (Cellectis) uses genetically modified allogeneic T-Cells (derived from healthy donors, so-called “off the shelf”) containing an anti-CD123 CAR and a RQR8 depletion ligand that confers susceptibility to rituximab. The expression of the T-Cell receptor (TCR) is abrogated through the inactivation of the TCRα constant gene, using Cellectis9 TALEN® gene-editing technology. We have previously reported the selective in vitro anti-tumor activity of UCART123 Cells against CD123+ primary BPDCN samples using cytotoxicity assays, T-Cell degranulation assay and the secretion of IFNγ and other cytokines (IL2, IL5, IL6, IL-13 and TNF-α) by UCART123 Cells when cultured in the presence of BPDCN Cells (Tianyu Cai, 2017 ASH). However, UCART123 had minimum toxicity against normal bone marrow Cells. To evaluate in vivo anti-tumor activity of UCART123 Cells, we established two patient-derived xenografts (PDX1-2) from patients with relapsed BPDCN in NSG-SGM3 mice. In PDX-1 model, all mice in vehicle-treated group died by D53, with high tumor burden in peripheral blood, spleen and bone marrow. Three out of 9 (33%) mice treated with 3×106 UCART123 and Six out of 9 (67%) mice treated with 10×106 UCART123 were alive and disease-free at the end of the study (D299). In PDX-2 model, while UCART123 similarly extended survival of the mice (D104-241), relapses occurred in all treatment cohorts at D90-155. Flow cytometric analysis showed that all of the relapses were associated with emergence of CD123- BPDCN clones (95-96% CD123-). To understand the molecular basis for loss of CD123 surface expression, we isolated RNA from two CD123 positive samples from vehicle group and two CD123 negative samples from 1×106 UCART123 group. RT-PCR and RNA-seq detected the presence of full-length transcripts containing exons 1-12 in both CD123 positive samples. In one of the two CD123 (-) samples, CD123 transcripts were completely absent, along with loss of transcripts of neighboring genes. In another CD123 (-) sample, CD123 transcripts containing only exons 1-9 were detected, indicating the presence of a truncation. Interestingly, if translated, this transcript would produce a protein isoform lacking the transmembrane domain (Ex 10). In summary, UCART123 therapy results in BPDCN eradication and long-term disease-free survival in a subset of primary BPDCN PDX models. However, loss of CD123 through diverse genetic mechanisms could lead to escape from UCART123 therapy and cause relapses. A phase I trial of UCART123 in BPDCN is opened for enrollment (NCT03203369). Citation Format: Tianyu Cai, Kathryn L. Black, Ammar Naqvi, Roman Galetto, Agnes Gouble, Julianne Smith, Antonio Cavazos, Lina Han, Qi Zhang, Vinitha Kuruvilla, Sergej Naumovich Sergej Konoplev, Sattva S. Neelapu, Andrew A. Lane, Monica L. Guzman, Hagop Kantarjian, Andrei Thomas-Tikhonenko, Naveen Pemmaraju, Marina Konopleva. Preclinical efficacy of allogeneic anti-CD123 CAR T-Cells for the therapy of blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2560.
Gabriel K Griffin - One of the best experts on this subject based on the ideXlab platform.
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sex biased zrsr2 mutations in myeloid malignancies impair Plasmacytoid Dendritic Cell activation and apoptosis
Cancer Discovery, 2021Co-Authors: Katsuhiro Togami, Gabriel K Griffin, Lucia Cabalhierro, Sun Sook Chung, Vikas Madan, Christopher A G Booth, Christopher M Kenyon, Justin Taylor, Sunhee S Kim, Mahmoud GhandiAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is an aggressive leukemia of Plasmacytoid Dendritic Cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation.
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sex biased zrsr2 mutations in myeloid malignancies impair Plasmacytoid Dendritic Cell activation and apoptosis
bioRxiv, 2020Co-Authors: Katsuhiro Togami, Gabriel K Griffin, Lucia Cabalhierro, Sun Sook Chung, Vikas Madan, Christopher M Kenyon, Justin Taylor, Sunhee S KimAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is an aggressive leukemia of Plasmacytoid Dendritic Cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. STATEMENT OF SIGNIFICANCESex bias in cancer is well recognized but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs Dendritic Cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.
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comprehensive metagenomic analysis of blastic Plasmacytoid Dendritic Cell neoplasm
Blood Advances, 2020Co-Authors: Jason Nomburg, Gabriel K Griffin, Katsuhiro Togami, Elizabeth A Morgan, Nicole R Leboeuf, Susan Bullman, Sun Sook Chung, Mark Walker, James A Decaprio, Matthew MeyersonAbstract:: Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from Plasmacytoid Dendritic Cells (pDCs), the immune Cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN Cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-Cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel Cell polyomavirus in Merkel Cell carcinoma, human papillomavirus in head and neck squamous Cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
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blastic Plasmacytoid Dendritic Cell neoplasm is dependent on bcl2 and sensitive to venetoclax
Cancer Discovery, 2017Co-Authors: Joan Montero, Jason Stephansky, Gabriel K Griffin, Lucia Cabalhierro, Katsuhiro Togami, Leah Hogdal, Ilene Galinsky, Elizabeth A Morgan, Jon C Aster, Matthew S. DavidsAbstract:Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN Cells were dependent on the anti-apoptotic protein BCL-2 and were uniformly sensitive to the BCL-2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo. Finally, we report on two patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL-2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.
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blastic Plasmacytoid Dendritic Cell neoplasm bpdcn is highly bcl 2 dependent and sensitive to venetoclax
Blood, 2016Co-Authors: Joan Montero, Jason Stephansky, Gabriel K Griffin, Lucia Cabalhierro, Katsuhiro Togami, Leah Hogdal, Ilene Galinsky, Nicole R Leboeuf, Tianyu Cai, Jon C AsterAbstract:Abstract Blastic Plasmacytoid Dendritic Cell neoplasm (BPDCN) is a particularly aggressive hematologic malignancy with median survival of 80% bone marrow blasts. His BPDCN carried the mutations ASXL1 Y581fs*, ASXL1 E553fs*, GNB1 K57E, IDH2 R140W, and NRAS G12D, and expressed high levels of BCL-2 protein in bone marrow and skin. BH3 profiling of a skin tumor biopsy revealed marked BCL-2 dependence and dynamic BH3 response to venetoclax (4 hr delta priming 55.6%). We treated him using a regimen recently FDA-approved for chronic lymphocytic leukemia (CLL) consisting of weekly dose escalation (20 -> 50 -> 100 -> 200 mg), to a target dose of 400 mg daily. At the time of this writing, he had reached 200 mg without significant toxicity, including no evidence of tumor lysis syndrome. His skin disease has responded remarkably (Figure), with the first response evident within 10 days. Our data suggests that BPDCN is highly sensitive to BCL-2 inhibition, which could provide an urgently needed new treatment for patients with this disease. We propose that BCL-2 inhibition should undergo expedited clinical evaluation in BPDCN. In addition, this case offers an example of precision cancer medicine by functional rather than genetic means. Download : Download high-res image (97KB) Download : Download full-size image Disclosures Davids: Infinity: Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Stone: ONO: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Letai: AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding. Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding.