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Omar Abdel-Wahab

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https://www.readbyqxmd.com/read/28801450/genomic-analysis-of-hairy-cell-leukemia-identifies-novel-recurrent-genetic-alterations
#1
Benjamin H Durham, Bartlomiej Getta, Sascha Dietrich, Justin Taylor, Helen Won, James M Bogenberger, Sasinya Scott, Eunhee Kim, Young Rock Chung, Stephen S Chung, Jennifer Hüllein, Tatjana Walther, Lu Wang, Sydney X Lu, Christopher C Oakes, Raoul Tibes, Torsten Haferlach, Barry S Taylor, Martin S Tallman, Michael F Berger, Jae H Park, Thorsten Zenz, Omar Abdel-Wahab
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation while ~30% of variant HCL (vHCL) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1- wildtype vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n=53) and vHCL (n=8). The most common genetic alteration in cHCL outside of BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wildtype BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation...
August 11, 2017: Blood
https://www.readbyqxmd.com/read/28748614/novel-activating-braf-fusion-identifies-a-recurrent-alternative-mechanism-for-erk-activation-in-pediatric-langerhans-cell-histiocytosis
#2
Sara Zarnegar, Benjamin H Durham, Pallavi Khattar, Neerav N Shukla, Ryma Benayed, Mario E Lacouture, Ehud Lavi, David C Lyden, Eli L Diamond, Ira J Dunkel, Omar Abdel-Wahab
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism...
July 27, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28679734/high-prevalence-of-myeloid-neoplasms-in-adults-with-non-langerhans-cell-histiocytosis
#3
Matthias Papo, Eli L Diamond, Fleur Cohen-Aubart, Jean-François Emile, Damien Roos-Weil, Nishant Gupta, Benjamin H Durham, Neval Ozkaya, Ahmet Dogan, Gary A Ulaner, Raajit Rampal, Jean-Emmanuel Kahn, Thomas Sené, Frédéric Charlotte, Baptiste Hervier, Caroline Besnard, Olivier A Bernard, Catherine Settegrana, Nathalie Droin, Zofia Hélias-Rodzewicz, Zahir Amoura, Omar Abdel-Wahab, Julien Haroche
Erdheim-Chester Disease (ECD) is a rare non-Langerhans Cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAP kinase signaling. Due to the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans Cell Histiocytosis (so-called Mixed Histiocytosis (MH)), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms amongst patients with ECD and MH...
July 5, 2017: Blood
https://www.readbyqxmd.com/read/28673397/identification-and-targeting-of-kinase-alterations-in-histiocytic-neoplasms
#4
REVIEW
Neval Ozkaya, Ahmet Dogan, Omar Abdel-Wahab
Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28600336/diagnosis-and-classification-of-hematologic-malignancies-on-the-basis-of-genetics
#5
REVIEW
Justin Taylor, Wenbin Xiao, Omar Abdel-Wahab
Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia...
July 27, 2017: Blood
https://www.readbyqxmd.com/read/28576879/robust-patient-derived-xenografts-of-mds-mpn-overlap-syndromes-capture-the-unique-characteristics-of-cmml-and-jmml
#6
Akihide Yoshimi, Maria E Balasis, Alexis Vedder, Kira Feldman, Yan Ma, Hailing Zhang, Stanley Chun-Wei Lee, Christopher Letson, Sandrine Niyongere, Sydney X Lu, Markus Ball, Justin Taylor, Qing Zhang, Yulong Zhao, Salma Youssef, Young Rock Chung, Xiao Jing Zhang, Benjamin H Durham, Wendy Yang, Alan F List, Mignon L Loh, Virginia Klimek, Michael F Berger, Elliot Stieglitz, Eric Padron, Omar Abdel-Wahab
Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγ(null) background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML...
July 27, 2017: Blood
https://www.readbyqxmd.com/read/28566492/functional-evidence-for-derivation-of-systemic-histiocytic-neoplasms-from-hematopoietic-stem-progenitor-cells
#7
Benjamin H Durham, Damien Roos-Weil, Claude Baillou, Fleur Cohen-Aubart, Akihide Yoshimi, Makoto Miyara, Matthias Papo, Zofia Hélias-Rodzewicz, Nathalie Terrones, Neval Ozkaya, Ahmet Dogan, Raajit Rampal, Fanny Urbain, Lucie Le Fèvre, Eli L Diamond, Christopher Y Park, Thomas Papo, Frédéric Charlotte, Guy Gorochov, Valérie Taly, Olivier A Bernard, Zahir Amoura, Omar Abdel-Wahab, François M Lemoine, Julien Haroche, Jean-François Emile
Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive...
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28553668/the-clinical-spectrum-of-erdheim-chester-disease-an-observational-cohort-study
#8
Juvianee I Estrada-Veras, Kevin J O'Brien, Louisa C Boyd, Rahul H Dave, Benjamin Durham, Liqiang Xi, Ashkan A Malayeri, Marcus Y Chen, Pamela J Gardner, Jhonell R Alvarado-Enriquez, Nikeith Shah, Omar Abdel-Wahab, Bernadette R Gochuico, Mark Raffeld, Elaine S Jaffe, William A Gahl
Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations...
February 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/28545085/splicing-factor-sf3b1k700e-mutant-dysregulates-erythroid-differentiation-via-aberrant-alternative-splicing-of-transcription-factor-tal1
#9
Shuiling Jin, Hairui Su, Ngoc-Tung Tran, Jing Song, Sydney S Lu, Ying Li, Suming Huang, Omar Abdel-Wahab, Yanyan Liu, Xinyang Zhao
More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an RNA binding protein, RBM15, stronger than the wild type SF3B1 protein in co-immunoprecipitation assays...
2017: PloS One
https://www.readbyqxmd.com/read/28516957/asxl2-is-essential-for-haematopoiesis-and-acts-as-a-haploinsufficient-tumour-suppressor-in-leukemia
#10
Jean-Baptiste Micol, Alessandro Pastore, Daichi Inoue, Nicolas Duployez, Eunhee Kim, Stanley Chun-Wei Lee, Benjamin H Durham, Young Rock Chung, Hana Cho, Xiao Jing Zhang, Akihide Yoshimi, Andrei Krivtsov, Richard Koche, Eric Solary, Amit Sinha, Claude Preudhomme, Omar Abdel-Wahab
Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28512190/hematopoietic-origin-of-langerhans-cell-histiocytosis-and-erdheim-chester-disease-in-adults
#11
Paul Milne, Venetia Bigley, Chris M Bacon, Antoine Néel, Naomi McGovern, Simon Bomken, Muzlifah Haniffa, Eli L Diamond, Benjamin H Durham, Johannes Visser, David Hunt, Harsha Gunawardena, Mac Macheta, Kenneth L McClain, Carl Allen, Omar Abdel-Wahab, Matthew Collin
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAF(V600E) mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAF(V600E) allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL...
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28468827/hmg-coa-synthase-1-is-a-synthetic-lethal-partner-of-braf-v600e-in-human-cancers
#12
Liang Zhao, Jun Fan, Siyuan Xia, Yaozhu Pan, Shuangping Liu, Guoqing Qian, Zhiyu Qian, Hee-Bum Kang, Jack L Arbiser, Brian P Pollack, Ragini R Kudchadkar, David H Lawson, Michael Rossi, Omar Abdel-Wahab, Taha Merghoub, Hanna J Khoury, Fadlo R Khuri, Lawrence H Boise, Sagar Lonial, Fangping Chen, Jing Chen, Ruiting Lin
Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAF(V600E) up-regulates HMG-CoA lyase (HMGCL), which converts HMG-CoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAF(V600E)-dependent MEK1 activation in human cancer...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28466384/splicing-factor-mutations-in-mds-rars-and-mds-mpn-rs-t
#13
REVIEW
Akihide Yoshimi, Omar Abdel-Wahab
Spliceosomal mutations, especially mutations in SF3B1, are frequently (>80%) identified in patients with refractory anemia with ringed sideroblasts (RARS) and myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T; previously known as RARS-T), and SF3B1 mutations have a high positive predictive value for disease phenotype with ringed sideroblasts. These observations suggest that SF3B1 mutations play important roles in the pathogenesis of these disorders and formation of ringed sideroblasts...
June 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28408421/modeling-cbl-activating-mutations-in-vivo
#14
Stanley Chun-Wei Lee, Omar Abdel-Wahab
No abstract text is available yet for this article.
April 13, 2017: Blood
https://www.readbyqxmd.com/read/28348147/how-do-messenger-rna-splicing-alterations-drive-myelodysplasia
#15
REVIEW
Poorval Joshi, Stephanie Halene, Omar Abdel-Wahab
Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS.
May 4, 2017: Blood
https://www.readbyqxmd.com/read/28330793/outcomes-in-transcatheter-aortic-valve-replacement-for-bicuspid-versus-tricuspid%C3%A2-aortic%C3%A2-valve-stenosis
#16
MULTICENTER STUDY
Sung-Han Yoon, Sabine Bleiziffer, Ole De Backer, Victoria Delgado, Takahide Arai, Johannes Ziegelmueller, Marco Barbanti, Rahul Sharma, Gidon Y Perlman, Omar K Khalique, Erik W Holy, Smriti Saraf, Florian Deuschl, Buntaro Fujita, Philipp Ruile, Franz-Josef Neumann, Gregor Pache, Masao Takahashi, Hidehiro Kaneko, Tobias Schmidt, Yohei Ohno, Niklas Schofer, William K F Kong, Edgar Tay, Daisuke Sugiyama, Hiroyuki Kawamori, Yoshio Maeno, Yigal Abramowitz, Tarun Chakravarty, Mamoo Nakamura, Shingo Kuwata, Gerald Yong, Hsien-Li Kao, Michael Lee, Hyo-Soo Kim, Thomas Modine, S Chiu Wong, Francesco Bedgoni, Luca Testa, Emmanuel Teiger, Christian Butter, Stephan M Ensminger, Ulrich Schaefer, Danny Dvir, Philipp Blanke, Jonathon Leipsic, Fabian Nietlispach, Mohamed Abdel-Wahab, Bernard Chevalier, Corrado Tamburino, David Hildick-Smith, Brian K Whisenant, Seung-Jung Park, Antonio Colombo, Azeem Latib, Susheel K Kodali, Jeroen J Bax, Lars Søndergaard, John G Webb, Thierry Lefèvre, Martin B Leon, Raj Makkar
BACKGROUND: Transcatheter aortic valve replacement (TAVR) is being increasingly performed in patients with bicuspid aortic valve stenosis (AS). OBJECTIVES: This study sought to compare the procedural and clinical outcomes in patients with bicuspid versus tricuspid AS from the Bicuspid AS TAVR multicenter registry. METHODS: Outcomes of 561 patients with bicuspid AS and 4,546 patients with tricuspid AS were compared after propensity score matching, assembling 546 pairs of patients with similar baseline characteristics...
May 30, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28304277/partial-loss-of-genes-might-open-therapeutic-window
#17
Bo Liu, Omar Abdel-Wahab
The loss of genes that encode RNA splicing factors weakens cancer cells in a way that could be exploited by new approaches to treatment.
March 17, 2017: ELife
https://www.readbyqxmd.com/read/28214412/histiocytoses-emerging-neoplasia-behind-inflammation
#18
REVIEW
Julien Haroche, Fleur Cohen-Aubart, Barret J Rollins, Jean Donadieu, Frédéric Charlotte, Ahmed Idbaih, Augusto Vaglio, Omar Abdel-Wahab, Jean-François Emile, Zahir Amoura
Histiocytoses are disorders characterised by inflammation and the accumulation of cells derived from the monocyte and macrophage lineages, which results in tissue damage. Although they are often considered rare disorders with protean clinical manifestations, considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions, and fuelled further insights into their pathogenesis. In this Review, we describe insights into the cells of origin, molecular pathology, clinical features, and treatment strategies for some of the most common histiocytic disorders, including Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease...
February 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28089569/prevention-of-dietary-fat-fueled-ketogenesis-attenuates-braf-v600e-tumor-growth
#19
Siyuan Xia, Ruiting Lin, Lingtao Jin, Liang Zhao, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Guoqing Qian, Zhiyu Qian, Evmorfia Konstantakou, Baotong Zhang, Jin-Tang Dong, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Lu Zhou, Ragini R Kudchadkar, David H Lawson, Hanna J Khoury, Fadlo R Khuri, Lawrence H Boise, Sagar Lonial, Benjamin H Lee, Brian P Pollack, Jack L Arbiser, Jun Fan, Qun-Ying Lei, Jing Chen
Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice...
February 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/27903528/consensus-guidelines-for-the-diagnosis-and-management-of-patients-with-classic-hairy-cell-leukemia
#20
Michael R Grever, Omar Abdel-Wahab, Leslie A Andritsos, Versha Banerji, Jacqueline Barrientos, James S Blachly, Timothy G Call, Daniel Catovsky, Claire Dearden, Judit Demeter, Monica Else, Francesco Forconi, Alessandro Gozzetti, Anthony D Ho, James B Johnston, Jeffrey Jones, Gunnar Juliusson, Eric Kraut, Robert J Kreitman, Loree Larratt, Francesco Lauria, Gerard Lozanski, Emili Montserrat, Sameer A Parikh, Jae H Park, Aaron Polliack, Graeme R Quest, Kanti R Rai, Farhad Ravandi, Tadeusz Robak, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine Tam, Enrico Tiacci, Xavier Troussard, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani, Brunangelo Falini
Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease...
February 2, 2017: Blood
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