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Omar Abdel-Wahab

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https://www.readbyqxmd.com/read/29192649/the-histopathology-of-erdheim-chester-disease-a-comprehensive-review-of-a-molecularly-characterized-cohort
#1
Neval Ozkaya, Marc K Rosenblum, Benjamin H Durham, Janine D Pichardo, Omar Abdel-Wahab, Meera R Hameed, Klaus J Busam, William D Travis, Eli L Diamond, Ahmet Dogan
Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series...
December 1, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29188284/vemurafenib-for-braf-v600-mutant-erdheim-chester-disease-and-langerhans-cell-histiocytosis-analysis-of-data-from-the-histology-independent-phase-2-open-label-ve-basket-study
#2
Eli L Diamond, Vivek Subbiah, A Craig Lockhart, Jean-Yves Blay, Igor Puzanov, Ian Chau, Noopur S Raje, Jurgen Wolf, Joseph P Erinjeri, Jean Torrisi, Mario Lacouture, Elena Elez, Ferran Martínez-Valle, Benjamin Durham, Maria E Arcila, Gary Ulaner, Omar Abdel-Wahab, Bethany Pitcher, Martina Makrutzki, Todd Riehl, José Baselga, David M Hyman
Importance: The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study...
November 29, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29097875/trends-and-outcomes-of-pancreaticoduodenectomy-for-periampullary-tumors-a-25-year-single-center-study-of-1000-consecutive-cases
#3
Ayman El Nakeeb, Waleed Askar, Ehab Atef, Ehab El Hanafy, Ahmad M Sultan, Tarek Salah, Ahmed Shehta, Mohamed El Sorogy, Emad Hamdy, Mohamed El Hemly, Ahmed A El-Geidi, Tharwat Kandil, Mohamed El Shobari, Talaat Abd Allah, Amgad Fouad, Mostafa Abu Zeid, Ahmed Abu El Eneen, Nabil Gad El-Hak, Gamal El Ebidy, Omar Fathy, Ahmed Sultan, Mohamed Abdel Wahab
AIM: To evaluate the evolution, trends in surgical approaches and reconstruction techniques, and important lessons learned from performing 1000 consecutive pancreaticoduodenectomies (PDs) for periampullary tumors. METHODS: This is a retrospective review of the data of all patients who underwent PD for periampullary tumor during the period from January 1993 to April 2017. The data were categorized into three periods, including early period (1993-2002), middle period (2003-2012), and late period (2013-2017)...
October 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28958291/therapeutic-targeting-of-rna-splicing-in-myelodysplasia
#4
REVIEW
Young Joon Kim, Omar Abdel-Wahab
Genomic analysis of patients with myelodysplastic syndromes (MDS) has identified that mutations within genes encoding RNA splicing factors represent the most common class of genetic alterations in MDS. These mutations primarily affect SF3B1, SRSF2, U2AF1, and ZRSR2. Current data suggest that these mutations perturb RNA splicing catalysis in a manner distinct from loss of function but how exactly the global changes in RNA splicing imparted by these mutations result in MDS is not well delineated. At the same time, cells bearing mutations in RNA splicing factors are exquisitely dependent on the presence of the remaining wild-type (WT) allele to maintain residual normal splicing for cell survival...
July 2017: Seminars in Hematology
https://www.readbyqxmd.com/read/28854169/a-somatic-mutation-in-erythro-myeloid-progenitors-causes-neurodegenerative-disease
#5
Elvira Mass, Christian E Jacome-Galarza, Thomas Blank, Tomi Lazarov, Benjamin H Durham, Neval Ozkaya, Alessandro Pastore, Marius Schwabenland, Young Rock Chung, Marc K Rosenblum, Marco Prinz, Omar Abdel-Wahab, Frederic Geissmann
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration...
September 21, 2017: Nature
https://www.readbyqxmd.com/read/28801450/genomic-analysis-of-hairy-cell-leukemia-identifies-novel-recurrent-genetic-alterations
#6
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, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type 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 apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation...
October 5, 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
#7
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
#8
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 MAPK signaling. Because of 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 among patients with ECD and MH...
August 24, 2017: Blood
https://www.readbyqxmd.com/read/28673397/identification-and-targeting-of-kinase-alterations-in-histiocytic-neoplasms
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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. BRAFV600E 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, BRAFV600E 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
#17
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
#18
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
#19
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
#20
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
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