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Genetics on myeloproliferative disease

Brianna N Smith, Michael Savona, Rami S Komrokji
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hybrid group of chronic myeloid neoplasms combining features of both MDS and MPN. The World Health Organization classification coined this group designation in 2008 to include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomoncoytic leukemia, refractory anemia with ring sideroblasts and thrombocytosis as a provisional entity, and MDS/MPN unclassified. In this review, we highlight the challenges in diagnosing this group of the diseases, summarize the updates in classification, and discuss recent evolving understanding of the genetic landscape...
January 2019: Clinical Lymphoma, Myeloma & Leukemia
Jennifer O'Sullivan, Adam J Mead
Myeloproliferative neoplasms (MPNs) are haematopoietic stem cell-derived clonal disorders characterised by proliferation of some or all myeloid lineages, depending on the subtype. MPNs are classically categorized into three disease subgroups; essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). The majority (>85%) of patients carry a disease-initiating or driver mutation, the most prevalent occurring in the janus kinase 2 gene (JAK2 V617F), followed by calreticulin (CALR) and myeloproliferative leukaemia virus (MPL) genes...
November 22, 2018: Advances in Biological Regulation
Brian Chipman Belyea, Fang Xu, Maria Luisa Soledad Sequeira-Lopez, Roberto Ariel Gomez
Conditional deletion of RBP-J , the major transcriptional effector of Notch signaling, specifically within renin-expressing cells leads to the development of B cell leukemia. However, the influence of contributing factors such as mouse strain, cell of origin, and cre recombinase copy number are unknown. In this study, we compared RBP-J deletion efficiency using 1 versus 2 copies of cre recombinase. Further, we compared the incidence and timing of leukemia development in two unique strains of mice, C57BL/6 and 129/Sv, as well as at different B cell developmental stages...
November 22, 2018: Disease Models & Mechanisms
Jane Jialu Xu, Monique F Smeets, Shuh Ying Tan, Meaghan Wall, Louise E Purton, Carl R Walkley
Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2, and U2AF1 mutations...
November 6, 2018: Experimental Hematology
Ana P Azevedo, Susana N Silva, Alice Reichert, Fernando Lima, Esmeraldina Júnior, José Rueff
Several single nucleotide polymorphisms (SNPs) influencing DNA repair capacity and apoptotic status may confer genetic predisposition to Philadelphia‑chromosome negative myeloproliferative neoplasms (PN‑MPNs), and influence therapeutic response and the clinical course. In the present study, whether SNPs in genes involved in apoptosis and the base excision repair (BER) pathway was evaluated. In addition, some known risk factors in PN‑MPNs that may influence survival and therapeutic response to hydroxyurea (HU) were analyzed, taking into account three items: Disease progression, predisposition to new non‑myeloid neoplasms and thrombotic events...
December 2018: Molecular Medicine Reports
Kotaro Shide
One of the main molecular features of myeloproliferative neoplasms (MPNs) is the high frequency of JAK2V617F or CALRexon 9 mutations. The mouse models driven by these mutations suggest that they are the direct cause of MPNs and that the expression levels of mutated genes define the disease phenotype. The function of MPN-initiating cells was also elucidated using these mouse models. Furthermore, these mouse models play important roles as disease models to investigate the effects and mechanisms of action of therapeutic drugs such as JAK2 inhibitors and interferon α against MPNs...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Jacob Grinfeld, Jyoti Nangalia, E Joanna Baxter, David C Wedge, Nicos Angelopoulos, Robert Cantrill, Anna L Godfrey, Elli Papaemmanuil, Gunes Gundem, Cathy MacLean, Julia Cook, Laura O'Neil, Sarah O'Meara, Jon W Teague, Adam P Butler, Charlie E Massie, Nicholas Williams, Francesca L Nice, Christen L Andersen, Hans C Hasselbalch, Paola Guglielmelli, Mary F McMullin, Alessandro M Vannucchi, Claire N Harrison, Moritz Gerstung, Anthony R Green, Peter J Campbell
BACKGROUND: Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. METHODS: We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes...
October 11, 2018: New England Journal of Medicine
Fulya Öz Puyan, Serhan Alkan
With increasing characterization of disease associated molecular markers, it is becoming challenging to perform multiple single-gene molecular assays. Specific molecular markers are helpful for diagnostic, prognostic evaluation and management of hematologic malignancies. Introduction and rapid progress on next generation sequencing has led to extensive modifications and offers a novel way to integrate concurrent assessment of multiple target genes in routine laboratory analysis especially in view of increasing clinical demands for testing of multiple genetic aberrations...
September 25, 2018: Balkan Medical Journal
Katya Hristova Uzunova, Elena Pavlova Filipova, Toni Yonkov Vekov
Aim of Study: This review aims to highlight that bosutinib represents a valuable alternative for patients already treated unsuccessfully with one or more other tyrosine kinase inhibitors (TKIs). Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm associated with a specific genetic abnormality resulting in a fusion protein with an active tyrosine kinase region. Therefore, TKIs were developed as a suitable treatment option. Methods: Full-text articles, abstracts, and meta-analysis comparing the efficacy and safety of the five TKIs were included in the review...
July 2018: Journal of Cancer Research and Therapeutics
Lane H Miller, Cheng-Kui Qu, Melinda Pauly
The relationship between the hematopoietic stem cell (HSC) population and its surrounding bone marrow microenvironment is a rapidly evolving area of research. Normal HSC processes rely heavily on a complex communication network involving various marrow niches. Although leukemogenesis largely results from abnormal genetic activity within the leukemia stem cell itself, mounting evidence indicates a significant contributory role played by marrow niche dysregulation. Furthermore, numerous instances of activating or inactivating germline mutations within marrow microenvironment cells have been shown to be sufficient for development of myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia, even in the context of wild-type HSCs...
October 2018: Experimental Hematology
Ayalew Tefferi
DISEASE OVERVIEW: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional disease features include bone marrow stromal reaction including reticulin fibrosis, abnormal cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival...
December 2018: American Journal of Hematology
Aliasghar Keramatinia, Alireza Ahadi, Mohammad Esmaeil Akbari, Maryam Mohseny, Alireza Mosavi Jarahi, Ayad Bahadori-Monfared, Mehrdad Hashemi, Afshin Moradi, Narjes Mehrvar, Elham Kazemi, Abolfazl Movafagh
Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22) (q34;q11.2) encoding for the BCR-ABL fusion oncogene. Growing body of evidence suggests that epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukemic clone escape and disease propagation. The significant of therapeutic role in chronic myeloid leukemia (CML) depends on both genetic and epigenetic mechanisms.  This article focused on the CML and epigenetic and clinical significance...
June 30, 2018: Cellular and Molecular Biology
Prajwal Boddu, Dai Chihara, Lucia Masarova, Naveen Pemmaraju, Keyur P Patel, Srdan Verstovsek
Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by proliferation of one or more elements of the myeloid lineage. Key genetic aberrations include the BCR-ABL1 gene rearrangement in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and JAK2/MPL/CALR aberrations in Philadelphia chromosome-negative MPNs. While thought to be mutually exclusive, occasional isolated reports of coexistence of BCR-ABL1 and JAK2, and JAK2 with MPL or CALR aberrations have been described. Given the paucity of data, clinical characteristics and outcome of patients harboring concurrent Philadelphia-positive and Philadelphia-negative mutations or dual Philadelphia-negative driver mutations have not been systematically evaluated, and their clinical relevance is largely unknown...
November 2018: Annals of Hematology
Michael Asger Andersen, Ole Weis Bjerrum, Ajenthen Ranjan, Vibe Skov, Torben A Kruse, Mads Thomassen, Axel Skytthe, Hans Carl Hasselbalch, Kaare Christensen
OBJECTIVE: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. METHOD: All twin pairs born in the period 1900-2010 were identified in the nationwide Danish Twin Registry...
2018: Acta Haematologica
Richa Chauhan, Sudha Sazawal, H P Pati
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by translocation of genetic material from chromosome 9 to chromosome 22 to form a fusion gene (BCR-ABL1) that is responsible for abnormal tyrosine kinase activity and alteration of various downstream signaling pathways. In addition to morphological diagnosis of CML phase, it is essential to detect BCR-ABL1 fusion by either metaphase cytogenetics or reverse transcriptase polymerase chain reaction that also determines type of mRNA transcript...
April 2018: Indian Journal of Hematology & Blood Transfusion
Jackline P Ayres-Silva, Martin H Bonamino, Maria E Gouveia, Barbara C R Monte-Mor, Diego F Coutinho, Adelmo H Daumas, Cristiana Solza, Esteban Braggio, Ilana Renault Zalcberg
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases...
2018: Frontiers in Oncology
Natasha Szuber, Ayalew Tefferi
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies...
February 13, 2018: Blood Cancer Journal
Elias Jabbour, Hagop Kantarjian
DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome...
March 2018: American Journal of Hematology
Marie Lindgren, Jan Samuelsson, Lars Nilsson, Håvar Knutsen, Waleed Ghanima, Johan Westin, Peter L Johansson, Björn Andréasson
OBJECTIVE: In myeloproliferative neoplasms (MPN), interferon-alpha (IFN-α) is an effective treatment with disease-modifying properties but currently with no clear predictors of treatment outcome. Recent genomewide association studies in chronic hepatitis C have found a strong influence of genetic polymorphism near the IL28B (IFNL3) gene in response to IFN-α treatment. In this study, we sought to evaluate the prognostic impact of IL28B rs12979860, rs8099917, and rs12980275 on IFN-α treatment response in myeloproliferative neoplasms...
May 2018: European Journal of Haematology
Craig R Soderquist, Mark D Ewalt, David R Czuchlewski, Julia T Geyer, Heesun J Rogers, Eric D Hsi, Sa A Wang, Carlos E Bueso-Ramos, Attilio Orazi, Daniel A Arber, Elizabeth O Hexner, Daria V Babushok, Adam Bagg
Myeloproliferative neoplasms arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of myeloproliferative neoplasms is based on hematologic, histopathologic and molecular characteristics including the presence of the BCR-ABL1 and JAK2 V617F. Although thought to be mutually exclusive, a number of cases with co-occurring BCR-ABL1 and JAK2 V617F have been identified. To characterize the clinicopathologic features of myeloproliferative neoplasms with concomitant BCR-ABL1 and JAK2 V617F, and define the frequency of co-occurrence, we conducted a retrospective multi-institutional study...
May 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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