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Ann Mullally

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https://read.qxmd.com/read/30504299/jak2-and-other-genes-be-nimble-with-mpn-diagnosis-prognosis-and-therapy
#1
REVIEW
Michele Ciboddo, Ann Mullally
Now that the spectrum of somatic mutations that initiate, propagate, and drive the progression of myeloproliferative neoplasms (MPNs) has largely been defined, recent efforts have focused on integrating this information into clinical decision making. In this regard, the greatest progress has been made in myelofibrosis, in which high-molecular-risk mutations have been identified and incorporated into prognostic models to help guide treatment decisions. In this chapter, we focus on advances in 4 main areas: (1) What are the MPN phenotypic driver mutations? (2) What constitutes high molecular risk in MPN (focusing on ASXL1 )? (3) How do we risk-stratify patients with MPN? And (4) What is the significance of molecular genetics for MPN treatment? Although substantial progress has been made, we still have an incomplete understanding of the molecular basis for phenotypic diversity in MPN, and few rationally designed therapeutic approaches to target high-risk mutations are available...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
https://read.qxmd.com/read/30504235/the-kinases-ikbke-and-tbk1-regulate-myc-dependent-survival-pathways-through-yb-1-in-aml-and-are-targets-for-therapy
#2
Suhu Liu, Anna E Marneth, Gabriela Alexe, Sarah R Walker, Helen I Gandler, Darwin Q Ye, Katherine Labella, Radhika Mathur, Patricia A Toniolo, Michelle Tillgren, Prafulla C Gokhale, David Barbie, Ann Mullally, Kimberly Stegmaier, David A Frank
To identify novel therapeutic targets in acute myeloid leukemia (AML), we examined kinase expression patterns in primary AML samples. We found that the serine/threonine kinase IKBKE, a noncanonical IkB kinase, is expressed at higher levels in myeloid leukemia cells compared with normal hematopoietic cells. Inhibiting IKBKE, or its close homolog TANK-binding kinase 1 (TBK1), by either short hairpin RNA knockdown or pharmacological compounds, induces apoptosis and reduces the viability of AML cells. Using gene expression profiling and gene set enrichment analysis, we found that IKBKE/TBK1-sensitive AML cells typically possess an MYC oncogenic signature...
December 11, 2018: Blood Advances
https://read.qxmd.com/read/30075132/gli1-mesenchymal-stromal-cells-are-a-key-driver-of-bone-marrow-fibrosis-and-an-important-cellular-therapeutic-target
#3
Rebekka K Schneider, Ann Mullally, Aurelien Dugourd, Fabian Peisker, Remco Hoogenboezem, Paulina M H Van Strien, Eric M Bindels, Dirk Heckl, Guntram Büsche, David Fleck, Gerhard Müller-Newen, Janewit Wongboonsin, Monica Ventura Ferreira, Victor G Puelles, Julio Saez-Rodriguez, Benjamin L Ebert, Benjamin D Humphreys, Rafael Kramann
No abstract text is available yet for this article.
August 2, 2018: Cell Stem Cell
https://read.qxmd.com/read/29643232/increased-neutrophil-extracellular-trap-formation-promotes-thrombosis-in-myeloproliferative-neoplasms
#4
Ofir Wolach, Rob S Sellar, Kimberly Martinod, Deya Cherpokova, Marie McConkey, Ryan J Chappell, Alexander J Silver, Dylan Adams, Cecilia A Castellano, Rebekka K Schneider, Robert F Padera, Daniel J DeAngelo, Martha Wadleigh, David P Steensma, Ilene Galinsky, Richard M Stone, Giulio Genovese, Steven A McCarroll, Bozenna Iliadou, Christina Hultman, Donna Neuberg, Ann Mullally, Denisa D Wagner, Benjamin L Ebert
Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling...
April 11, 2018: Science Translational Medicine
https://read.qxmd.com/read/29364275/using-crispr-cas9-gene-editing-to-investigate-the-oncogenic-activity-of-mutant-calreticulin-in-cytokine-dependent-hematopoietic-cells
#5
Nouran S Abdelfattah, Ann Mullally
Clustered regularly interspaced short palindromic repeats (CRISPR) is an adaptive immunity system in prokaryotes that has been repurposed by scientists to generate RNA-guided nucleases, such as CRISPR-associated (Cas) 9 for site-specific eukaryotic genome editing. Genome engineering by Cas9 is used to efficiently, easily and robustly modify endogenous genes in many biomedically-relevant mammalian cell lines and organisms. Here we show an example of how to utilize the CRISPR/Cas9 methodology to understand the biological function of specific genetic mutations...
January 5, 2018: Journal of Visualized Experiments: JoVE
https://read.qxmd.com/read/29288169/defining-the-requirements-for-the-pathogenic-interaction-between-mutant-calreticulin-and-mpl-in-mpn
#6
Shannon Elf, Nouran S Abdelfattah, April J Baral, Danielle Beeson, Jeanne F Rivera, Amy Ko, Natalie Florescu, Gabriel Birrane, Edwin Chen, Ann Mullally
Mutations in calreticulin ( CALR ) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth...
February 15, 2018: Blood
https://read.qxmd.com/read/28673398/kinase-inhibitors-in-the-treatment-of-myeloid-malignancies
#7
EDITORIAL
Ann Mullally
No abstract text is available yet for this article.
August 2017: Hematology/oncology Clinics of North America
https://read.qxmd.com/read/28673391/the-development-and-use-of-janus-kinase-2-inhibitors-for-the-treatment-of-myeloproliferative-neoplasms
#8
REVIEW
Gabriela S Hobbs, Sarah Rozelle, Ann Mullally
Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera...
August 2017: Hematology/oncology Clinics of North America
https://read.qxmd.com/read/28457748/gli1-mesenchymal-stromal-cells-are-a-key-driver-of-bone-marrow-fibrosis-and-an-important-cellular-therapeutic-target
#9
Rebekka K Schneider, Ann Mullally, Aurelien Dugourd, Fabian Peisker, Remco Hoogenboezem, Paulina M H Van Strien, Eric M Bindels, Dirk Heckl, Guntram Büsche, David Fleck, Gerhard Müller-Newen, Janewit Wongboonsin, Monica Ventura Ferreira, Victor G Puelles, Julio Saez-Rodriguez, Benjamin L Ebert, Benjamin D Humphreys, Rafael Kramann
Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1+ mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1+ cells abolished BMF and rescued bone marrow failure...
June 1, 2017: Cell Stem Cell
https://read.qxmd.com/read/28159736/myeloproliferative-neoplasm-stem-cells
#10
REVIEW
Adam J Mead, Ann Mullally
Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: JAK2 , CALR , or MPL The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells...
March 23, 2017: Blood
https://read.qxmd.com/read/27712165/editorial
#11
(no author information available yet)
SO WEare to have new chief nursing officers (CNOs) for England and Scotland. Sarah Mullally's surprise resignation last month paves the way for a new leader in England, while Paul Martin has been appointed Anne Jarvie's successor in Scotland. Maybe a new era for nurse leadership is in the offing?
July 1, 2004: Nursing Management (Harrow)
https://read.qxmd.com/read/27622333/physiologic-expression-of-sf3b1-k700e-causes-impaired-erythropoiesis-aberrant-splicing-and-sensitivity-to-therapeutic-spliceosome-modulation
#12
Esther A Obeng, Ryan J Chappell, Michael Seiler, Michelle C Chen, Dean R Campagna, Paul J Schmidt, Rebekka K Schneider, Allegra M Lord, Lili Wang, Rutendo G Gambe, Marie E McConkey, Abdullah M Ali, Azra Raza, Lihua Yu, Silvia Buonamici, Peter G Smith, Ann Mullally, Catherine J Wu, Mark D Fleming, Benjamin L Ebert
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1(K700E). Sf3b1(K700E) mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1(K700E) myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay...
September 12, 2016: Cancer Cell
https://read.qxmd.com/read/26951227/mutant-calreticulin-requires-both-its-mutant-c-terminus-and-the-thrombopoietin-receptor-for-oncogenic-transformation
#13
Shannon Elf, Nouran S Abdelfattah, Edwin Chen, Javier Perales-Patón, Emily A Rosen, Amy Ko, Fabian Peisker, Natalie Florescu, Silvia Giannini, Ofir Wolach, Elizabeth A Morgan, Zuzana Tothova, Julie-Aurore Losman, Rebekka K Schneider, Fatima Al-Shahrour, Ann Mullally
UNLABELLED: Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition...
April 2016: Cancer Discovery
https://read.qxmd.com/read/26686625/recql5-suppresses-oncogenic-jak2-induced-replication-stress-and-genomic-instability
#14
Edwin Chen, Jong Sook Ahn, David B Sykes, Lawrence J Breyfogle, Anna L Godfrey, Jyoti Nangalia, Amy Ko, Daniel J DeAngelo, Anthony R Green, Ann Mullally
JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs). Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU), a pharmacological inducer of replication stress and the most common treatment for MPNs...
December 22, 2015: Cell Reports
https://read.qxmd.com/read/26569382/targeting-megakaryocytic-induced-fibrosis-in-myeloproliferative-neoplasms-by-aurka-inhibition
#15
Qiang Jeremy Wen, Qiong Yang, Benjamin Goldenson, Sébastien Malinge, Terra Lasho, Rebekka K Schneider, Lawrence J Breyfogle, Rachael Schultz, Laure Gilles, Priya Koppikar, Omar Abdel-Wahab, Animesh Pardanani, Brady Stein, Sandeep Gurbuxani, Ann Mullally, Ross L Levine, Ayalew Tefferi, John D Crispino
Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis...
December 2015: Nature Medicine
https://read.qxmd.com/read/26537747/haemophagocytic-lymphohistiocytosis-in-adults-a-multicentre-case-series-over-7-years
#16
MULTICENTER STUDY
Alison M Schram, Paige Comstock, Meghan Campo, Daniel Gorovets, Ann Mullally, Kelly Bodio, Jon Arnason, Nancy Berliner
Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T-cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH...
February 2016: British Journal of Haematology
https://read.qxmd.com/read/25696866/how-does-jak2v617f-contribute-to-the-pathogenesis-of-myeloproliferative-neoplasms
#17
REVIEW
Edwin Chen, Ann Mullally
A decade on from the discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms (MPNs), JAK2V617F is now firmly installed in the hematology curriculum of medical students and the diagnostic-testing algorithm of clinicians. Furthermore, the oral JAK1/JAK2 inhibitor ruxolitinib, rationally designed to target activated JAK2 signaling in MPN, has been approved by the Food and Drug Administration (FDA) of the United States for the past 3 years for the treatment of intermediate- and advanced-phase myelofibrosis...
December 5, 2014: Hematology—the Education Program of the American Society of Hematology
https://read.qxmd.com/read/25573993/marked-hyperferritinemia-does-not-predict-for-hlh-in-the-adult-population
#18
Alison M Schram, Federico Campigotto, Ann Mullally, Annemarie Fogerty, Elena Massarotti, Donna Neuberg, Nancy Berliner
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of uncontrolled immune activation that has gained increasing attention during the last decade. The diagnosis of HLH is based on a constellation of clinical and laboratory abnormalities, including elevated serum ferritin levels. In the pediatric population, marked hyperferritinemia is specific for HLH. To determine what conditions are associated with profoundly elevated ferritin in the adult population, we performed a retrospective analysis in a large academic health care system...
March 5, 2015: Blood
https://read.qxmd.com/read/25552701/role-of-the-clathrin-adaptor-picalm-in-normal-hematopoiesis-and-polycythemia-vera-pathophysiology
#19
Yuichi Ishikawa, Manami Maeda, Mithun Pasham, Francois Aguet, Silvia K Tacheva-Grigorova, Takeshi Masuda, Hai Yi, Sung-Uk Lee, Jian Xu, Julie Teruya-Feldstein, Maria Ericsson, Ann Mullally, John Heuser, Tom Kirchhausen, Takahiro Maeda
Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type-specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis...
April 2015: Haematologica
https://read.qxmd.com/read/25468568/dynamin-2-dependent-endocytosis-is-required-for-normal-megakaryocyte-development-in-mice
#20
Markus Bender, Silvia Giannini, Renata Grozovsky, Terese Jönsson, Hilary Christensen, Fred G Pluthero, Amy Ko, Ann Mullally, Walter H A Kahr, Karin M Hoffmeister, Hervé Falet
Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2(fl/fl) Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2(fl/fl) Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance...
February 5, 2015: Blood
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