scholarly journals Thrombocytosis in children and adolescents—classification, diagnostic approach, and clinical management

2021 ◽  
Author(s):  
Clemens Stockklausner ◽  
◽  
C. M. Duffert ◽  
H. Cario ◽  
R. Knöfler ◽  
...  
Keyword(s):  
Clinical Management ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Pediatric Population ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Gene Encoding ◽  
Clinical Complications ◽  
Genes Encoding ◽  
Infection And Inflammation

AbstractSecondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor’s effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

scholarly journals Hippo Pathway-related Genes Expression Is Deregulated in Myeloproliferative Neoplasms

2021 ◽  
Author(s):  
Maira da Costa Cacemiro ◽  
Juçara Gastaldi Cominal ◽  
Luiz Miguel Pereira ◽  
Maria Gabriela Berzoti-Coelho ◽  
Giovana Michelassi Berbel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Hippo Pathway ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Hippo Signaling ◽  
Apoptosis Resistance ◽  
Hematological Disorders

Abstract Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased proliferation of precursor and mature myeloid cells. MPN patients may present driver mutations in JAK2, MPL, and CALR genes, which are essential to describe the molecular mechanisms of MPN pathogenesis. Despite all the new knowledge on MPN pathogenesis, many questions remain to be answered to develop effective therapies to cure MPN or impair its progression to acute myeloid leukemia. The present study examined the expression levels of the Hippo signaling pathway members in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as the role that they play in disease pathogenesis. The Hippo pathway is a tumor suppressor pathway that participates in the regulation of cell proliferation, differentiation, and death. Our main findings were: (i) expression of tumor suppressor genes from Hippo pathway were downregulated and seemed to be associated with cell resistance to apoptosis and increased proliferation rate; and (ii) Hippo pathway-related gene expression was associated with mutation status in ET and PMF patients. Therefore, the decreased expression of Hippo pathway-related genes may contribute to the malignant phenotype, apoptosis resistance, and cell proliferation in MPN pathogenesis.

scholarly journals Three tightly linked genes encoding human type I keratins: conservation of sequence in the 5'-untranslated leader and 5'-upstream regions of coexpressed keratin genes.

1986 ◽  
Vol 6 (2) ◽  
pp. 539-548 ◽  
Author(s):  
A RayChaudhury ◽  
D Marchuk ◽  
M Lindhurst ◽  
E Fuchs
Keyword(s):  
Molecular Mechanisms ◽  
Type I ◽  
Differential Splicing ◽  
Gene Encoding ◽  
Linked Gene ◽  
Human Dna ◽  
Human Epidermal Cells ◽  
Genes Encoding ◽  
Positive Hybridization ◽  
Endonuclease Mapping

We have isolated and subcloned three separate segments of human DNA which share strong sequence homology with a previously sequenced gene encoding a type I keratin, K14 (50 kilodaltons). Restriction endonuclease mapping has demonstrated that these three genes are tightly linked chromosomally, whereas the K14 gene appears to be separate. As judged by positive hybridization-translation and Northern blot analyses, the central linked gene encodes a keratin, K17, which is expressed in abundance with K14 and two other type I keratins in cultured human epidermal cells. None of these other epidermal keratin mRNAs appears to be generated from the K17 gene through differential splicing of its transcript. The sequence of the K17 gene reveals striking homologies not only with the coding portions and intron positions of the K14 gene, but also with its 5'-noncoding and 5'-upstream sequences. These similarities may provide an important clue in elucidating the molecular mechanisms underlying the coexpression of the two genes.

scholarly journals Prefibrotic Myelofibrosis Presenting with Multiple Cerebral Embolic Infarcts and the Rare MPL W515S Mutation

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Lisa Lee Tokar ◽  
Laura Kearney ◽  
Cathal O’Brien ◽  
Kowshika Thavarajah ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Common Mutation ◽  
Limited Information ◽  
Phenotypic Data ◽  
Activating Mutations ◽  
Cerebral Event

Acquired, activating mutations of MPL W515 are recognised driver mutations of the myeloproliferative neoplasms (MPN), namely, essential thrombocythemia and primary myelofibrosis. The most common mutation at this codon is W515L with several other mutations also described at a lower frequency. Of these less common mutations, MPL W515S has only been reported sporadically with limited information on clinicopathological associations. We describe the case of an elderly man with persistent thrombocytosis presenting with an ischemic cerebral event. Bone marrow biopsy showed evidence of prefibrotic myelofibrosis with targeted sequencing demonstrating the presence of the rare MPL W515S mutation. Thrombolytic and cytoreductive therapies resulted in a favorable outcome and follow-up. This case provides additional, necessary, and phenotypic data for the rare MPN-associated MPL W515S mutation.

Latium (Italy) Epidemiology of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs) from 2011 to 2015: A Prospective Analysis from Gruppo Laziale of Ph Negative MPN

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5473-5473
Author(s):  
Marianna De Muro ◽  
Ambra Di Veroli ◽  
Marco Montanaro ◽  
Roberto Latagliata ◽  
Cristina Santoro ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Community Based ◽  
Thrombotic Risk ◽  
Inflammatory Bowel ◽  
Perspective Analysis ◽  
Observation Period

Abstract Background: MPNs including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hematopoietic diseases in which the discovery of molecular driver mutations (JAK2, CALR, MPL) has deeply modified diagnostic approach in recent years. To date available data on epidemiology of MPNs and perspective analysis are rare. Our aim is to study the incidence of MPN Ph negative in a specific region of Italy named Latium and its variability across five years. Moreover we prospectively report the general features of our population. Method: We present here the prospective epidemiologic analysis of 1116 adult patients affected by MPNs (PV=289, ET=550, PMF=209) diagnosed according to 2008 WHO criteria, from January 2011 to December 2015 in 15 hematological Centers (5 academic and 10 community-based Hospitals) in Latium. A total of 289 PV, 550 ET and 209PMF were identified. The overall incidence rate of 289PV was 1.0/105 in 2011 and 2012, 1.1/105 in 2013, 0.9/105 in 2014 and 2015. The overall incidence rate of 550ET was 2.0/105 in 2011, 2.4/105 in 2012, 2.2/105 in 2013, 1.8/105 in 2014 and 1,2/105 in 2015 and the overall incidence rate of 209PMF was 0.7/105 in 2011 and 2012, 1.0/105 in 2013, 0.7/105 in 2014 and 0.5/105 in 2015. We have observed also 63 cases of MPNu (36M/32F) and the incidence rate was 0.3/105 in 2011 and 2012, 0.14/105 in 2013, 0.24/105 in 2014 and 0.22/105 in 2015. Baseline features of PV, ET and PMF patients are summarized in table 1. We have also analyzed the presence of comorbidities including obesity, arhythmia and neoplasia observed at the diagnosis in 1.6, 6.2 and 4% of all population, respectively; thirty-five percent of 1116 pts presented other comorbidities such as diabetes, inflammatory bowel disease, renal and liver failure. As thrombotic risk factors we considered diabetes, dislipidemia, smoke, essential hypertension and thrombophilia observed in 11,8, 16,2, 13,2, 51,7 and 3% of total pts, respectively. Conclusions: We confirm in our prospective observational protocol the overall incidence of MPN Ph negative, previously reported in the literature and the major incidence of male gender in PV and PMF, female in of ET. The annual incidence from 2011-2015 in Latium is remained substantially the same during the observation period. The decreasing trend observed in 2015 is probably due to the different update of some Centers that was done in October 2015 not including patients diagnosed in the last two months. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria.

scholarly journals The role of JAK2 inhibitors in MPNs 7 years after approval

Blood ◽  
2018 ◽  
Vol 131 (22) ◽  
pp. 2426-2435 ◽  
Author(s):  
Francesco Passamonti ◽  
Margherita Maffioli
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Symptom Relief ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Volume Response ◽  
Symptom Response ◽  
Definition Of ◽  
Jak2 Inhibitors

Abstract Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV), and primary myelofibrosis (MF). Phenotype-driver mutations of JAK2, CALR, and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high-risk MF and for PV inadequately controlled by or intolerant of hydroxyurea. Other JAKis, such as fedratinib and pacritinib, proved to be useful in MF. The primary end points in MF trials were spleen volume response (SVR) and symptom response, whereas in PV trials they were hematocrit control with or without spleen response. In advanced MF, RUX achieved a long lasting SVR of >35% in ∼60% of patients, establishing a new benchmark for MF treatment. RUX efficacy in early MF is also remarkable and toxicity is mild. In PV, RUX achieved hematocrit control in ∼60% of cases and SVR in 40%. Symptom relief was evident in both conditions. In the long-term, however, many MF patients lose their SVR. Indeed, the definition of RUX failure and the design of new trials in this setting are unmet needs. Decrease of hemoglobin/platelet levels and increased infection rates are the most common side effects of RUX, and nonmelanoma skin tumors need to be monitored while on treatment. In conclusion, the introduction of JAKis raises the bar of treatment goals in MF and PV.

From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms

Blood ◽  
2014 ◽  
Vol 123 (24) ◽  
pp. 3714-3719 ◽  
Author(s):  
Mario Cazzola ◽  
Robert Kralovics
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Mutation Status ◽  
Genomic Landscape ◽  
Exon 10 ◽  
Stat Pathway

Abstract Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials.

scholarly journals A myeloid tumor suppressor role for NOL3

2017 ◽  
Vol 214 (3) ◽  
pp. 753-771 ◽  
Author(s):  
Robert F. Stanley ◽  
Richard T. Piszczatowski ◽  
Boris Bartholdy ◽  
Kelly Mitchell ◽  
Wendy M. McKimpson ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Underlying Disease ◽  
Driver Mutations ◽  
Stem Cell Population ◽  
Myeloid Malignancies ◽  
Cd34 Cells ◽  
Oncogenic Driver ◽  
Molecular Aberrations

Despite the identification of several oncogenic driver mutations leading to constitutive JAK–STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3−/− MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3−/−-induced JAK–STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and Myc. Nol3−/− MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.

Diagnostic and Therapeutic MicroRNAs in Primary Myelofibrosis

2020 ◽  
Vol 14 (02) ◽  
pp. 91-109
Author(s):  
Roxana Manaila ◽  
Vlad Moisoiu ◽  
Erik Knutsen ◽  
Mihnea P. Dragomir ◽  
George A. Calin
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Symptom Control ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
In Vivo Studies ◽  
Driver Mutations ◽  
Transcriptional Level ◽  
Hematopoietic Stem ◽  
Medical Needs

Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2, CALR, or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature microRNAs (miRNAs) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger RNAs at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific miRNAs, as well as complex miRNA networks, to be dysregulated in PMF. Several of these miRNAs were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose miRNAs as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.

scholarly journals Recent advances in understanding myelofibrosis and essential thrombocythemia

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 700 ◽  
Author(s):  
William Vainchenker ◽  
Stefan N. Constantinescu ◽  
Isabelle Plo
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Great Majority ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
New Therapeutic Approaches ◽  
Recent Advances ◽  
Downstream Effectors ◽  
Thrombopoietin Receptor

The classicBCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery ofCALRmutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient’s constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the development of JAK2 inhibitors.

scholarly journals Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yujie Chen ◽  
Rafee Talukder ◽  
Brian Y. Merritt ◽  
Katherine Y. King ◽  
Marek Kimmel ◽  
...  
Keyword(s):  
Case Report ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Genomic Data ◽  
Myelogenous Leukemia ◽  
Driver Mutations ◽  
Ancestral Reconstruction ◽  
Hematopoietic Stem ◽  
Molecular Abnormalities

Abstract Background We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration. Case presentation A 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation. Conclusions The use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.

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