Aberrant expression of SPAG6 may affect the disease phenotype and serve as a tumor biomarker in BCR/ABL1‑negative myeloproliferative neoplasms

Polo-like kinases (Plks) are critical regulatory molecules during the cell cycle process. This family has five members: Plk1, 2, 3, 4, and 5. Plk4 has been identified as a master regulator of centriole replication, and its aberrant expression is closely associated with cancer development. In this review, we depict the DNA, mRNA, and protein structure of Plk4, and the regulation of Plk4 at a molecular level. Then we list the downstream targets of Plk4 and the hallmarks of cancer associated with these targets. The role of Plk4 in different cancers is also summarized. Finally, we review the inhibitors that target Plk4 in the hope of discovering effective anticancer drugs. From authors’ perspective, Plk4 might represent a valuable tumor biomarker and critical target for cancer diagnosis and therapy.

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JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F–positive essential thrombocythemia

Blood ◽

10.1182/blood-2009-12-259747 ◽

2010 ◽

Vol 116 (9) ◽

pp. 1528-1538 ◽

Cited By ~ 136

Author(s):

Juan Li ◽

Dominik Spensberger ◽

Jong Sook Ahn ◽

Shubha Anand ◽

Philip A. Beer ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Essential Thrombocythemia ◽

Cell Function ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Jak2 V617f ◽

Transgenic Models ◽

Disease Phenotype ◽

Hematopoietic Stem

The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.

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Total Platelet Transcriptomics and Its Network Analysis by RNA-Seq and miRNA-Seq and PCA Application in Essential Thrombocythaemia

Acta Haematologica ◽

10.1159/000510459 ◽

2020 ◽

pp. 1-8

Author(s):

Kyung Chul Moon ◽

Jeong-An Gim ◽

Dae Sik Kim ◽

Chul Won Choi ◽

Jung Yoon ◽

...

Keyword(s):

Regulatory Network ◽

Target Genes ◽

Thrombus Formation ◽

Myeloproliferative Neoplasms ◽

Expression Patterns ◽

Principal Component ◽

Inverse Correlation ◽

Essential Thrombocythaemia ◽

Aberrant Expression ◽

Healthy Control

Differentiating the aetiology of thrombocytosis is limited yet crucial in patients with essential thrombocythaemia (ET). MicroRNAs (miRNAs) regulate haematopoiesis and lineage commitment; aberrant expression of miRNAs plays an important role in myeloproliferative neoplasms. However, the miRNA profile has been poorly explored in ET patients compared to patients with reactive thrombocytosis (RT). A total of 9 samples, including 5 ET patient samples, 2 RT patient samples, and 2 healthy control samples, were analysed in this study. We produced 81.43 million reads from transcripts and 59.60 million reads from small RNAs. We generated a comprehensive miRNA-mRNA regulatory network and identified unique 14 miRNA expression patterns associated with ET. Among the 14 miRNAs, miR-1268a was downregulated in ET and showed an inverse correlation with its 8 putative target genes, including genes associated with thrombus formation and platelet activation (<i>CDH6, EHD2, FUT1, KIF26A, LINC00346, PTPRN, SERF1A,</i> and <i>SLC6A9</i>). Principal component analysis (PCA) showed ET and non-ET groups well clustered in space, suggesting each group had a distinctive expression pattern of mRNAs and miRNAs. These results suggest that the significant dysregulation of miR-1268a and its 8 target genes could be a unique expression of platelet miRNAs and miRNA/mRNA regulatory network in ET patients.

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In Myelodysplastic/Myeloproliferative Neoplasms Aberrant Antigen Expression As Assessed by Multiparameter Flow Cytometry Is Related to Molecular Genetic Mutations

Blood ◽

10.1182/blood.v118.21.5152.5152 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5152-5152

Author(s):

Wolfgang Kern ◽

Susanne Schnittger ◽

Tamara Alpermann ◽

Claudia Haferlach ◽

Torsten Haferlach

Keyword(s):

Myeloproliferative Neoplasms ◽

Molecular Genetic ◽

Antigen Expression ◽

Multiparameter Flow Cytometry ◽

Employment Equity ◽

Aberrant Expression ◽

Equity Ownership ◽

Diagnostic Work ◽

Work Up ◽

Diagnostic Work Up

Abstract Abstract 5152 Background: Immunophenotyping by multiparameter flow cytometry (MFC) is increasingly used in the diagnostic work-up of patients with cytopenias and suspected myelodysplastic syndromes (MDS). Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise a group of diseases with some features of MDS and is separately classified in the current WHO system. While the immunophenotype of chronic myelomonocytic leukemia has been described in detail, data is scarce on the use of MFC in myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPNu) as well as on refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), which is a provisional entity in the current WHO classification. Aim: To assess patients with MDS/MPNu and RARS-T for MDS-related aberrant immunophenotypes in the context of a comprehensive diagnostic work-up including cytomorphology, cytogenetics, and molecular genetics. Patients and Methods: A total of 91 patients were analyzed in parallel by cytomorphology, cytogenetics, and MFC applying an antibody panel designed to diagnose MDS. MFC was used to detect expression of mature antigens in myeloid progenitors; abnormal CD13-CD16- and CD11b-CD16-expression patterns, aberrant expression of myeloid markers and reduced side scatter signal in granulocytes; reduced expression of myelomonocytic markers in monocytes; aberrant expression of CD71 in erythroid cells; as well as expression of lymphoid markers in all myeloid cell lines. In 77/91 patients molecular genetic markers were investigated. The median age of the patients was 75.1 years (range, 35.3–87.4). The male/female ratio was 60/31. Six patients had RARS-T and 85 had MDS/MPNu. Results: In 54/91 (59.3%) patients MFC identified an MDS-immunophenotype. This was true in 4/6 (66.7%) RARS-T and in 50/85 (58.8%) MDS/MPNu (n.s.). Cases with MDS-immunophenotype displayed aberrancies significantly more frequently than those without as follows: in myeloid progenitor cells (number of aberrantly expressed antigens, mean±SD: 0.5±0.6 vs. 0.2±0.4, p=0.002), granulocytes (2.7±1.3 vs. 1.2±1.1, p<0.001), and monocytes (1.7±1.2 vs. 0.5±0.7, p<0.001). Accordingly, there was a significant difference in the total number of aberrantly expressed antigens (4.9±2.4 vs. 2.0±1.4, p<0.001). The presence of an aberrant karyotype was not related to an MDS-immunophenotype which was observed in 11/18 (61.1%) cases with aberrant karyotype and in 43/73 (58.9%) with normal karyotype (n.s.). Mutations in RUNX1 and TET2 as well as FLT3-ITD were predominantly present in cases with an MDS-immunophenotype (10/33, 30.3%) and occurred less frequently in cases without (1/7, 9.1%, n.s.). In detail, RUNX1 mutations were present in 4/26 (10.3%) vs. 0/2, TET2 mutations were present in 4/6 (66.7%) vs. 1/2 (50%), and FLT3-ITD was present in 3/29 (10.3%) vs. 0/5. Accordingly, in cases with RUNX1 or TET2 mutations or with FLT3-ITD a significantly higher number of aberrantly expressed antigens was observed as compared to cases with none of these mutations (mean±SD, 6.4±2.0 vs. 4.4±2.5, p=0.024). In contrast, JAK2V617F mutations occurred at identical frequencies in patients with and without MDS-immunophenotype (11/38, 28.9% vs. 9/31, 29.0%). Regarding prognosis, the presence of an MDS-immunophenotype had no impact on overall survival. Conclusions: These data demonstrates that MDS-related aberrant antigen expression is present in the majority of patients with RARS-T and MDS/MPNu. While there is no association between the presence of an MDS-immunophenotype and the detection of JAK2 mutations cases with an MDS-immunophenotype tended to more frequently carry mutations in RUNX1 and TET2 as well as FLT3-ITDs. These data therefore suggests that MDS/MPNu may be subdivided based on molecular genetics and on the immunophenotype into cases with MDS-related features and those without. Further analyses are needed to validate these findings and their potential significance in RARS-T. Disclosures: Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Mutations of E3 Ubiquitin Ligase Cbl Family Members Constitute a Novel Common Pathogenic Lesion in Myeloid Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.7503 ◽

2009 ◽

Vol 27 (36) ◽

pp. 6109-6116 ◽

Cited By ~ 149

Author(s):

Hideki Makishima ◽

Heather Cazzolli ◽

Hadrian Szpurka ◽

Andrew Dunbar ◽

Ramon Tiu ◽

...

Keyword(s):

Clinical Features ◽

Ubiquitin Ligase ◽

Tyrosine Kinases ◽

Myeloproliferative Neoplasms ◽

Uniparental Disomy ◽

E3 Ubiquitin Ligase ◽

Myelogenous Leukemia ◽

Juvenile Myelomonocytic Leukemia ◽

Aberrant Expression ◽

Myelomonocytic Leukemia

Purpose Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism.

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CD44 as a tumor biomarker and therapeutic target

Experimental Hematology and Oncology ◽

10.1186/s40164-020-00192-0 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Hanxiao Xu ◽

Mengke Niu ◽

Xun Yuan ◽

Kongming Wu ◽

Aiguo Liu

Keyword(s):

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Current Data ◽

Molecular Forms ◽

Tumor Biomarker ◽

Aberrant Expression ◽

Targeting Therapy ◽

Mesenchymal Transition ◽

Cancer Management

AbstractCD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.

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Role of JAK2 V617F mutation and aberrant expression of microRNA-143 in myeloproliferative neoplasms

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0858 ◽

2015 ◽

Vol 53 (7) ◽

Cited By ~ 5

Author(s):

Marco Benati ◽

Martina Montagnana ◽

Elisa Danese ◽

Giovanna De Matteis ◽

Dino Veneri ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Blood Cells ◽

Healthy Subjects ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Idiopathic Myelofibrosis ◽

Aberrant Expression ◽

Who 2008

AbstractMyeloproliferative neoplasms (MPNs) are clonal myeloid disorders characterized by the overproduction of mature blood cells. The pathogenetic hallmark of MPNs is the dysregulation of JAK-STAT signaling, usually associated with theIn total 78 patients with a clinical diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IM), made according to the WHO 2008 criteria, were included in the study. Twenty healthy subjects were checked as controls. Quantification ofThe miR-143 expression in MPNs patients was 2.97-fold higher than in controls.Our findings of aberrant miR-143 expression support the concept that factors other than

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Downregulation of the lncRNA RP11-432I5.4 inhibits tumorigenesis in the JAK2V617F-positive classic myeloproliferative neoplasms

10.21203/rs.3.rs-26428/v1 ◽

2020 ◽

Author(s):

Jie Zhou ◽

Hao Wu ◽

Wen-Jun Zhang ◽

Jian-Fei Fu ◽

Ai-Bin Liang

Keyword(s):

Myeloproliferative Neoplasms ◽

Xenograft Model ◽

Tumor Formation ◽

Aberrant Expression ◽

Phase Arrest ◽

Non Coding Rna ◽

Mouse Xenograft Model ◽

Novel Target ◽

Long Non Coding Rna

Abstract Background: Although aberrant expression of long non-coding RNA (lncRNA) is associated with many human cancers, little is known about its role in the JAK2V617F-positive classic myeloproliferative neoplasms (cMPNs). Methods: In this study, we performed a comprehensive analysis of lncRNAs in human cMPNs cells using a lncRNA cDNA microarray and identified the lncRNA RP11-432I5.4 acted as an effective factor in JAK2V617F-positive cMPN cells. Results: The lncRNA RP11-432I5.4 showed higher expression in cMPN patients, especially higher in JAK2V617F-positive cells compared with JAK2V617F-negative cells. Overexpression of lncRNA RP11-432I5.4 increased the proliferation of JAK2V617F-positive cells while downregulation of it decreased proliferation, promoted apoptosis and triggered S phase arrest of JAK2V617F-positive cells. Furthermore, in a mouse xenograft model, the silencing of lncRNARP11-432I5.4 repressed tumor formation in vivo. Conclusions: Taken together, these results revealed that lncRNA RP11-432I5.4 plays an important role in cMPN tumorigenesis and may be a potential novel target for treatment of JAK2V617F-positive cMPN patients.

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Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22116027 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6027

Author(s):

Swayam Prakash Srivastava ◽

Julie E. Goodwin ◽

Pratima Tripathi ◽

Keizo Kanasaki ◽

Daisuke Koya

Keyword(s):

Kidney Disease ◽

Large Scale ◽

Diabetic Kidney Disease ◽

Kidney Diseases ◽

Noncoding Rnas ◽

Therapeutic Targets ◽

Disease Phenotype ◽

Aberrant Expression ◽

Diabetic Kidney ◽

Health And Disease

Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease

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Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100160297 ◽

1990 ◽

Vol 48 (3) ◽

pp. 548-549

Author(s):

T. A. Stewart ◽

D. Liggitt ◽

S. Pitts ◽

L. Martin ◽

M. Siegel ◽

...

Keyword(s):

Type I Diabetes ◽

Disease Process ◽

Class Ii ◽

Class I ◽

Type I ◽

Aberrant Expression ◽

Mhc Molecules ◽

Endogenous Insulin ◽

Class Ii Mhc ◽

Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

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