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Pankaj Dwivedi, Kenneth D Greis
Granulocyte colony-stimulating factor is a hematopoietic cytokine that stimulates neutrophil production and hematopoietic stem cell mobilization by initiating the dimerization of homodimeric granulocyte colony-stimulating factor receptor. Different mutations of CSF3R have been linked to a unique spectrum of myeloid disorders and related malignancies. Myeloid disorders caused by the CSF3R mutations include severe congenital neutropenia, chronic neutrophilic leukemia, and atypical chronic myeloid leukemia. In this review, we provide an analysis of granulocyte colony-stimulating factor receptor, various mutations, and their roles in the severe congenital neutropenia, chronic neutrophilic leukemia, and malignant transformation, as well as the clinical implications and some perspective on approaches that could expand our knowledge with respect to the normal signaling mechanisms and those associated with mutations in the receptor...
October 24, 2016: Experimental Hematology
K-H Lim, Y-C Chang, Y-H Chiang, H-C Lin, C-Y Chang, C-S Lin, L Huang, W-T Wang, C Gon-Shen Chen, W-C Chou, Y-Y Kuo
CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b...
October 7, 2016: Blood Cancer Journal
B Jiang, J Y Qi, Q H Li, Y Xu, M Y Sun, W W Zheng, F Chen, L G Qiu
OBJECTIVE: To explored the diagnosis and treatment of chronic neutrophilic leukemia (CNL) complicated with multiple myeloma (MM). METHODS: The clinical features and molecular biological characteristics of 2 patients with CNL complicated with MM were summarized, and the diagnosis and treatment of the patients were retrospectively reviewed. RESULTS: The diagnosis of CNL complicated with MM was established in 2 cases. Case 1 had CSF3R mutation (P733T), but CSF3R-exon 14 mutation and SETBP1 mutation were all negative...
August 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Lawrence J Druhan, Daniel P McMahon, Nury Steuerwald, Andrea E Price, Amanda Lance, Jonathan M Gerber, Belinda R Avalos
No abstract text is available yet for this article.
August 31, 2016: Blood
Amaya Rando, Samanta Gasco, Miriam de la Torre, Alberto García-Redondo, Pilar Zaragoza, Janne M Toivonen, Rosario Osta
BACKGROUND: Amyotrophic lateral sclerosis (ALS) causes loss of upper and lower motor neurons as well as skeletal muscle (SKM) dysfunction and atrophy. SKM is one of the tissues involved in the development of ALS pathology, and studies in a SOD1-G93A mouse model of ALS have demonstrated alterations in SKM degeneration/regeneration marker expression in vivo and defective mutant myoblast proliferation in vitro. Granulocyte colony-stimulating factor (G-CSF) has been shown to alleviate SOD1-G93A pathology...
August 20, 2016: Neuro-degenerative Diseases
Jason H Fine, Genevieve S Bondy, Laurie Coady, Bevan Pearce, Nikia Ross, Azam F Tayabali, Sabina Halappanavar, Don Caldwell, Ivan Curran, David E Lefebvre
Humans could become exposed to carbon black nanoparticles (CBNPs) in consumer products or an occupational setting. In rodent models, acute respiratory, subcutaneous, and direct immune cell exposure to CBNPs has been shown to enhance allergic sensitization to co-administered ovalbumin (OVA) protein from chicken egg. However, little is known about the effects of ingested CBNPs on immunological responses and oral tolerance to food antigens. We hypothesized that ingestion of CBNPs would enhance the development of food allergy to OVA...
September 9, 2016: Nanotoxicology
Sang Mee Hwang, Seon Young Kim, Jung Ah Kim, Hee-Sue Park, Si Nae Park, Kyongok Im, Kwantae Kim, Sung-Min Kim, Dong Soon Lee
BACKGROUND: Telomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS...
2016: Journal of Hematology & Oncology
Subramaniam Agatheeswaran, Soumen Chakraborty
Chronic myelogenous leukemia (CML), a hematopoietic malignancy, characterized initially by a chronic phase (CP) progresses into blast crisis (BC) with the accumulation of secondary abnormalities. We have reported earlier that MEF2C, a target of miR-223, was significantly up regulated in CML and also showed a negative correlation with miR-223. In this study, gene expression arrays were used to identify the genes regulated by MEF2C during myelopoiesis. Statistical tools were used to understand the correlation between MEF2C and the targets in different phases of CML...
August 2016: International Journal of Biochemistry & Cell Biology
Maksim Klimiankou, Sabine Mellor-Heineke, Cornelia Zeidler, Karl Welte, Julia Skokowa
Acquired mutations in the intracellular part of CSF3R (colony stimulating factor 3 receptor, granulocyte) have been detected with a frequency of more than 30% in severe congenital neutropenia (CN) patients. CN is a preleukemic syndrome with a risk of approximately 20% to develop leukemia. More than 80% of CN patients who develop acute myeloid leukemia or myelodysplastic syndrome reveal CSF3R mutations, suggesting that they are involved in leukemogenesis. Using deep-sequencing technology, we were able to analyze large cohorts of CN patients for the entire CSF3R sequence as well as to identify cell clones carrying mutations in the intracellular part of CSF3R with very high sensitivity...
April 2016: Annals of the New York Academy of Sciences
Birgit Knoechel, Ami Bhatt, Li Pan, Chandra S Pedamallu, Eric Severson, Alejandro Gutierrez, David M Dorfman, Frank C Kuo, Michael Kluk, Andrew L Kung, Patrick Zweidler-McKay, Matthew Meyerson, Stephen C Blacklow, Daniel J DeAngelo, Jon C Aster
Notch pathway antagonists such as γ-secretase inhibitors (GSIs) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole-exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A...
October 2015: Cold Spring Harbor Molecular Case Studies
Julia E Maxson, Rhonda E Ries, Yi-Cheng Wang, Robert B Gerbing, E Anders Kolb, Sarah L Thompson, Jaime M Guidry Auvil, Marco A Marra, Yussanne Ma, Zusheng Zong, Andrew J Mungall, Richard Moore, William Long, Patee Gesuwan, Tanja M Davidsen, Leandro C Hermida, Seamus B Hughes, Jason E Farrar, Jerald P Radich, Malcolm A Smith, Daniela S Gerhard, Alan S Gamis, Todd A Alonzo, Soheil Meshinchi
No abstract text is available yet for this article.
June 16, 2016: Blood
Franc Llorens, Katrin Thüne, Matthias Schmitz, Belén Ansoleaga, Margalida A Frau-Méndez, Maria Cramm, Waqas Tahir, Nadine Gotzmann, Sara Berjaoui, Margarita Carmona, Christopher J Silva, Ivan Fernandez-Vega, Juan José Zarranz, Inga Zerr, Isidro Ferrer
Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. This study describes new neuropathological and biochemical observations in a series of eight patients with FFI. The mediodorsal and anterior nuclei of the thalamus have severe neuronal loss and marked astrocytic gliosis in every case, whereas the entorhinal cortex is variably affected...
April 7, 2016: Human Molecular Genetics
Vincent-Philippe Lavallée, Jana Krosl, Sébastien Lemieux, Geneviève Boucher, Patrick Gendron, Caroline Pabst, Isabel Boivin, Anne Marinier, Cynthia J Guidos, Sylvain Meloche, Josée Hébert, Guy Sauvageau
In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset...
June 16, 2016: Blood
Maksim Klimiankou, Sabine Mellor-Heineke, Olga Klimenkova, Elisa Reinel, Murat Uenalan, Siarhei Kandabarau, Julia Skokowa, Karl Welte, Cornelia Zeidler
No abstract text is available yet for this article.
May 26, 2016: Blood
Cigdem Aydogmus, Funda Cipe, Melda Tas, Aysenur Akinel, Özlem Öner, Gonca Keskindemirci, Helen Bornaun, Günsel Kutluk, Arzu Babayigit Hocaoglu
BACKGROUND: Mutations in the HAX-1 gene cause an autosomal recessive form of severe congenital neutropenia (SCN), which particularly manifests with recurrent skin, lung and deep tissue infections from the first few months of life. OBJECTIVE: We retrospectively evaluated the clinical and laboratory findings of the patients diagnosed with SCN carrying HAX1 gene mutations. METHODS: A total of five patients with SCN, carrying a HAX1 gene mutation, were evaluated in terms of clinical and laboratory findings...
March 2016: Asian Pacific Journal of Allergy and Immunology
Yi Xing, Ming-feng Zhao
Granulocyte colony stimulating factor (G-CSF) plays a major role in the proliferation, differentiation, and activation of neutrophil cell line hematopoietic cells. G-CSF exert the function depending on its binding to colony-stimulating factor 3 receptor (CSF3R), a homo-dimer receptor located on the surface of effector cells. Some recent studies have demonstrated that CSF3R mutations play a significant role in many diseases. Some of the hematopoietic diseases, especially myeloid malignancies (e.g. chronic neutrophilic leukemia) are related to the presence of various CSF3R mutations, which leads to abnormal G-CSF signal pathways...
February 2016: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Toru Mitsumori, Norio Komatsu, Keita Kirito
Chronic neutrophilic leukemia (CNL) is a rare form of myeloproliferative neoplasm characterized by the drastic elevation of mature neutrophils. One of the major causes of death among patients with CNL is severe bleeding; however, the difficulty of accurately diagnosing this disease has caused confusion in this field. Recently, somatic mutations of the CSF3R gene have been associated with CNL. This has led to the establishment of more accurate diagnostic criteria for CNL. We herein report a case study of a patient with CNL with a T618I point mutation on the CSF3R gene who showed severe bleeding...
2016: Internal Medicine
Michelle A Elliott, Ayalew Tefferi
Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 10(9) /L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R...
March 2016: American Journal of Hematology
Kim-Hien T Dao, Jeffrey W Tyner
Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding-our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms...
2015: Hematology—the Education Program of the American Society of Hematology
Ivo P Touw
Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue...
2015: Hematology—the Education Program of the American Society of Hematology
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