scholarly journals MPL W515 L/K mutations in myeloproliferative neoplasms

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sohaila Eldeweny ◽  
Hosny Ibrahim ◽  
Ghada Elsayed ◽  
Mohamed Samra
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Ethnic Groups ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Myelogenous Leukemia ◽  
Egyptian Population ◽  
Ph Chromosome ◽  
Pathological Variant

Abstract Background Myeloproliferative neoplasms (MPNs) describe a group of diseases involving the bone marrow (BM). Classical MPNs are classified into chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This classification is based on the presence of Philadelphia (Ph) chromosome (BCR/ABL1). CML is BCR/ABL1-positive while PV, ET, and PMF are negative. JAK2 p. Val617Phe pathological variant is the most associated mutation in BCR/ABL1-negative MPNs. The frequency of JAK2 p. Val617Phe is 90–95% in PV patients, 50–60% in ET, and 40–50% in patients with PMF. Studies on MPL gene led to the revelation of a gain of function pathological variants in JAK2 p. Val617Phe-negative myeloproliferative neoplasms (MPNs). MPL p. W515 L/K pathological variants are the most common across all mutations in MPL gene. The prevalence of these pathological variants over the Egyptian population is not clear enough. In the present study, we aimed to investigate the prevalence of MPL p. W515 L/K pathological variants in the Philadelphia (Ph)-negative MPNs over the Egyptian population. Results We have tested 60 patients with Ph-negative MPNs for MPL p. W515 L/K pathological variants. Median age was 51 (22–73) years. No MPL p. W515 L/K pathological variants were detected among our patients. JAK2 p. Val617Phe in PV and PMF patients showed significantly lower frequency than other studies. Splenomegaly was significantly higher in ET patients compared to other studies. Conclusion MPL p. W515 L/K pathological variants are rare across the Egyptian Ph-negative MPNs, and further studies on a large number are recommended. MPN patients in Egypt are younger compared to different ethnic groups.

scholarly journals Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study

2019 ◽  
Vol 11 (4) ◽  
Author(s):  
Vincenzo Accurso ◽  
Marco Santoro ◽  
Simona Raso ◽  
Angelo Davide Contrino ◽  
Paolo Casimiro ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Clinical Manifestations ◽  
Primary Myelofibrosis ◽  
Thrombotic Risk ◽  
Single Center Study ◽  
The Impact ◽  
The Relationship

Splenomegaly is one of the major clinical manifestations of primary myelofibrosis and is common also in other chronic Philadelphia-negative myeloproliferative neoplasms, causing symptoms and signs and affecting quality of life of patients diagnosed with these diseases. We aimed to study the impact that such alteration has on thrombotic risk and on the survival of patients with essential thrombocythemia and patients with Polycythemia Vera (PV). We studied the relationship between splenomegaly (and its grade), thrombosis and survival in 238 patients with et and 165 patients with PV followed at our center between January 1997 and May 2019.

Pegifna Promotes Proliferation and Myeloid Differentiation In Human Hematopoietic Progenitors In Patients With Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2843-2843
Author(s):  
Katherine King ◽  
Sabina Swierczek ◽  
Katie Matatall ◽  
Kimberly Hickman ◽  
Margaret A. Goodell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Hematopoietic Stem ◽  
Financial Compensation ◽  
Specific Differentiation ◽  
Allelic Burden

Abstract The myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET), are characterized by clonal hematopoiesis that is often associated with a JAK2V617F mutation, although this does not appear to be a disease-initiating event. Treatment of PV and ET with pegylated interferon-alpha (pegInfα) has been shown to lead to hematological remission, a decrease in the JAK2V617F allelic burden in many cases, and even a reversion to polyclonal hematopoiesis. Despite promising therapeutic results, the mechanism of pegInfα-induced remission remains elusive. There are several potential mechanisms through which pegInfα may be acting, which include stimulating the immune system in order to more effectively suppress the aberrant PV clones, enhancing the activation of normal hematopoietic stem cells (HSCs), or by selectively suppressing the mutant clones. It has been previously reported that PV patients on pegInfα have an increased number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in the peripheral blood as compared to untreated or hydroxyurea treated patients (Riley Blood, 2011), which suggests that PegIFNa maybe altering immunity against the mutated clone. However, we have found that interferon treatment leads to increased proliferation of HSCs and myeloid-specific differentiation in mice (Baldridge Nature, 2010). If this finding is also true in humans, it suggests the return to polyclonality after pegInfα could also involve an increase in normal HSC proliferation. In order to address this question, we are studying the effects of pegInfα treatment on the Tregs and HSCs of PV and EV patients, when compared to hydroxyurea or untreated patients. Previously we showed that pegInfα treatment reduced the JAK2V617F allelic burden in 17 out of 32 patients. Of the 13 female patients for which clonality could be assessed, one developed polyclonal hematopoiesis with three-fold reduction of JAK2V617F allelic burden, but one developed polyclonal hematopoiesis during therapy despite no reduction in the JAK2V617F allelic burden, suggesting that pegInfα treatment is able to affect both pre-JAK2V617F clones and JAK2V617F-positive PV clones. We have now assessed changes in the HSC population in response to pegInfα treatment. Upon analysis of bone marrow samples from these same pegInfα or hydroxyurea treated patients, we found that the number of HSCs (CD45+CD34+CD38-) was increased in patients treated with pegInfα. Further we saw a decrease in the percent of quiescent HSCs in the pegInfα treated samples, measured by the percentage of cells in G0, suggesting a more actively proliferating HSC population. In agreement with these data, our RNA analysis of the HSCs showed an increase in the expression of cell cycle genes in response to short-term pegInfα treatment. In addition to this apparent increase in HSC proliferation, we also saw an increase in the number of colonies formed in methocult media from the bone marrow samples of the pegInfα treated patients, suggesting an increase in myeloid specific differentiation. When we analyzed the RNA of patients who had received long-term pegInfα treatment, we saw a transcriptional profile that was indicative of cell death. Taken together, these data suggest a model in which pegInfα treatment is allowing for a return to polyclonal hematopoiesis by inducing cell division and differentiation of normal HSCs, while suppressing the pre-JAK2V617F or JAK2V617F-positive PV and ET clones, possibly by promoting apoptosis or inducing an immune-mediated cell death. Our findings do not exclude other potential mechanisms for salutary effects of pegInfα for treatment of PV and ET (see accompanying abstract by Swierczek et al). Disclosures: Swierczek: University of Utah: No financial compensation , No financial compensation Patents & Royalties.

scholarly journals Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5109-5117 ◽  
Author(s):  
Shu Xing ◽  
Tina Ho Wanting ◽  
Wanming Zhao ◽  
Junfeng Ma ◽  
Shaofeng Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Gene Promoter ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Transgenic Expression ◽  
Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

scholarly journals Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Daniele Cattaneo ◽  
Giorgio Alberto Croci ◽  
Cristina Bucelli ◽  
Silvia Tabano ◽  
Marta Giulia Cannone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Triple Negative ◽  
Clinical Laboratory ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Molecular Profile ◽  
Single Center ◽  
Driver Genes ◽  
Molecular Features

Lack of demonstrable mutations affecting JAK2, CALR, or MPL driver genes within the spectrum of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5–10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the TET2 gene (55.0%), followed by KIT (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.

High Mitochondrial Membrane Potential Identifies Patients with Myeloproliferative Neoplasms with a More Aggressive Natural History

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1992-1992
Author(s):  
Jeffrey R Gardner ◽  
Omar Abdel-Wahab ◽  
Mark Frattini ◽  
Joseph G Jurcic ◽  
Kristina Knapp ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Polycythemia Vera ◽  
Mitochondrial Membrane Potential ◽  
Essential Thrombocythemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Mitochondrial Membrane ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Acute Myeloid

Abstract Abstract 1992 The myeloproliferative neoplasms (MPN) can have a variable natural history. Polycythemia vera and essential thrombocythemia, in particular, are conditions that can extend over decades, but some patients have clinical progression to myelofibrosis or acute myeloid leukemia. As first articulated by Warburg, cancers are metabolically distinguished from normal tissues by the use of glycolysis under aerobic conditions. To metabolically characterize the blood cells of patients with myeloproliferative neoplasms, we measured the mitochondrial membrane potential using the cyanine dye, JC-1. In examining cells derived from the blood and/or marrow of 159 patients with primary myelofibrosis, polycythemia vera and essential thrombocythemia, we found that the mitochondrial membrane potential (FL2/FL1=electrochemical potential/mitochondrial mass) was elevated compared to the blood cells of normal individuals. Thirty five percent of patients with polycythemia vera and essential thrombocythemia had normal MMP. In contrast, 97% of patients with primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis and acute myeloid leukemia following an MPN had evidence of cell populations with higher mitochondrial membrane potential. Cells with distinctly higher mitochondrial membrane potential could be indentified in platelets and polymorphonuclear leukocytes; however the MMP of lymphocytes was normal, indicating that the alteration in metabolic state likely occurred in a multipotential myeloid stem cell. Cell populations were confirmed by co-staining with anti-CD19, -CD45, -GlycophorinA and -β3-integrin antibodies. Sequential analysis of patient samples found that the acquisition of higher mitochondrial membrane potential was stable and persistent over 2 years or more of follow up and that elevated membrane potential predisposed patients to disease progression. The balance of patients (65%) with ET had evidence of increased MMP suggesting the possibility of disease in an early state of evolution to a more aggressive condition. The increased MMP did not correlate with the presence of mutation in JAK2. These results indicate that clinically advanced MPN can be characterized by changes in mitochondrial physiology that might be identified non-invasively by flow cytometric staining with JC-1. In addition, the early nature of these changes may help to identify therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

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