scholarly journals Loss-of-function polymorphism in IL6R reduces risk of JAK2V617F somatic mutation and myeloproliferative neoplasm: A Mendelian randomization study

2020 ◽  
Vol 21 ◽  
pp. 100280 ◽  
Author(s):  
Kasper Mønsted Pedersen ◽  
Yunus Çolak ◽  
Christina Ellervik ◽  
Hans Carl Hasselbalch ◽  
Stig Egil Bojesen ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Mendelian Randomization ◽  
Myeloproliferative Neoplasm ◽  
Loss Of Function

scholarly journals Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Takuya Akiyama ◽  
Sırma D User ◽  
Matthew C Gibson
Keyword(s):  
Somatic Mutation ◽  
Cancer Genetics ◽  
Spontaneous Mutation ◽  
Tissue Level ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Cell Clones ◽  
Heterozygous Carriers ◽  
Disease Initiation ◽  
Central Paradigm

The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related ‘two-hit model’ remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila, we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations. Unexpectedly, four of these mutations had no phenotype in heterozygous carriers but exhibited clear tissue-level effects when present in somatic clones of heterozygous cells. We conclude that these alleles are indeed recessive when present in the germline, but nevertheless deleterious when present in heterozygous clones. This unforeseen effect, deleterious heteromosaicism, suggests a ‘one-hit’ mechanism for disease initiation that may explain some instances of pathogenesis associated with spontaneous mutation.

JAK1 somatic mutation in myeloproliferative neoplasm

Pathology ◽  
2018 ◽  
Vol 50 ◽  
pp. S104-S105
Author(s):  
Suzanne O. Arulogun ◽  
Hock-Choong Lai ◽  
Debbie Taylor ◽  
Paula Ambrosoli ◽  
Graham Magor ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Myeloproliferative Neoplasm

scholarly journals JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate

Haematologica ◽  
2014 ◽  
Vol 99 (9) ◽  
pp. 1448-1455 ◽  
Author(s):  
C. Nielsen ◽  
S. E. Bojesen ◽  
B. G. Nordestgaard ◽  
K. F. Kofoed ◽  
H. S. Birgens
Keyword(s):  
General Population ◽  
Somatic Mutation ◽  
Myeloproliferative Neoplasm ◽  
Progression Rate

scholarly journals Lipoprotein(a) and PCSK9 inhibition: clinical evidence

2020 ◽  
Vol 22 (Supplement_L) ◽  
pp. L53-L56 ◽  
Author(s):  
Massimiliano Ruscica ◽  
Maria Francesca Greco ◽  
Nicola Ferri ◽  
Alberto Corsini
Keyword(s):  
Clinical Evidence ◽  
Mendelian Randomization ◽  
High Plasma ◽  
Major Adverse Cardiovascular Events ◽  
Loss Of Function ◽  
Pcsk9 Inhibitors ◽  
Lipoprotein A ◽  
Strong Risk Factor ◽  
Pcsk9 Inhibition ◽  
Atherosclerotic Cardiovascular Diseases

Abstract Compelling evidence has emerged from epidemiological and Mendelian randomization analyses relative to the causality of lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular diseases (ASCVD), being elevated Lp(a) a strong risk factor regardless of the reduction of LDL-C achieved by statins. So far, no specific available agent can lower Lp(a) to the extent required to achieve a cardiovascular (CV) benefit, i.e. approximately 100 mg/dL. The most recent outcomes trial FOURIER with evolocumab showed that a 25 nmol/L (12 mg/dL) reduction in Lp(a) corresponded to a 15% decrement in the relative risk of cardiovascular disease. The ODYSSEY OUTCOMES trial with alirocumab has been the first demonstrating that a reduction in Lp(a) associates with less major adverse cardiovascular events (MACE), i.e. hazard ratio: 0.994 per 1 mg/dL decrement in Lp(a). The Lp(a) lowering effect driven by PCSK9 inhibition was confirmed in carriers of PCSK9 loss-of-function mutations in which Lp(a) and oxPL-apoB levels were decreased compared to non-carriers as was for a slight larger number of apo(a) Kringle IV repeats. Although PCSK9 inhibitors are not able to decrease Lp(a) to the extent required to achieve a CV benefit, their use has led to a higher discontinuation rate in lipoprotein apheresis in patients with progressive ASCVD and high plasma Lp(a).

Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21063-e21063
Author(s):  
Rachael Hagen ◽  
Joanna Amy Kolodney ◽  
Jessica Patterson ◽  
Michael Kolodney
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Somatic Mutation ◽  
Autosomal Dominant ◽  
Genetic Relationships ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Whole Exome ◽  
The Subject ◽  
Autosomal Dominant Inheritance Pattern

e21063 Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G > A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G > A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.

Calr Mutants Retroviral Mouse Models Lead to a Myeloproliferative Neoplasm Mimicking an Essential Thrombocythemia Progressing to a Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 157-157 ◽  
Author(s):  
Caroline Marty ◽  
Nivarthi Harini ◽  
Christian Pecquet ◽  
Ilyas Chachoua ◽  
Vitalina Gryshkova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
In Vivo Model ◽  
Common Mechanism ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Platelet Counts

Abstract Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis (PMF). They are malignant homeopathies resulting from the transformation of a multipotent hematopoietic stem cell (HSC). The common mechanism of transformation is the constitutive activation of the cytokine receptor/JAK2 pathway that leads to the myeloproliferation. The acquired point mutation JAK2V617F is the most prevalent (95% of PV and 60% of ET or PMF). In addition, other mutations affecting the same signaling pathway have been described such as JAK2 exon 12 mutations, mutations of MPL affecting W515, and loss-of-function mutations of LNK and also mutations of c-Cbl in 3% of PMF. Recently, whole exome sequencing allowed identifying a new recurrent genetic abnormalities in the exon 9 of the calreticulin gene (CALR) in about 30% of ET and PMF patients. All CALR mutants induce a frameshift of the same alternative reading frame and generate a novel C-terminus tail. To address the role of these new mutants in the pathophysiology of MPN, the goal of this study was to investigate the effect of the CALR mutant (del52 and ins5) expression by a retroviral mouse modeling. For that purpose, we transduced bone marrow cells with retrovirus expressing either CALRdel52, CALRins5, CALRWT or CALRDexon9 and performed a transplantation in lethally irradiated recipient mice (10 mice / group), which were then followed over one year. CALRdel52 expressing mice showed a rapid and strong increased in platelet counts (over 5 x106/mL) without any other changes in blood parameters during 6 months. In contrast, CALRins5 expressing mice presented platelet counts much lower than CALRdel52 but significantly higher than CALRWT or CALRDexon9 expressing mice. After 6 months, CALRdel52 expressing mice showed a decreased in platelets count associated with anemia and development of splenomegaly suggesting the progression to a myelofibrosis. Importantly, the disease was transplantable to secondary recipient for both CALRdel52 and CALRins5 mutants. The bone marrow and spleen were also analyzed over time. We observed a progressive increased in immature progenitors (SLAM cells) as well as a hypersensitivity of the megakaryocytic progenitors (CFU-MK) to thrombopoietin. Altogether, these results demonstrate that CALR mutants are able and sufficient to induce a thrombocytosis progressing to myelofibrosis in retroviral mouse model, thus mimicking the natural history of MPN patients. It will offer a good in vivo model to investigate therapeutic approaches for CALR-positive MPN. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tocilizumab and soluble interleukin-6 receptor in JAK2V617F somatic mutation and myeloproliferative neoplasm

2020 ◽  
Vol 22 ◽  
pp. 100337
Author(s):  
Kasper Mønsted Pedersen ◽  
Yunus Çolak ◽  
Hans Carl Hasselbalch ◽  
Stig Egil Bojesen ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Somatic Mutation ◽  
Interleukin 6 ◽  
Myeloproliferative Neoplasm ◽  
Interleukin 6 Receptor

scholarly journals JAK1 somatic mutation in a myeloproliferative neoplasm

Haematologica ◽  
2017 ◽  
Vol 102 (8) ◽  
pp. e324-e327 ◽  
Author(s):  
Suzanne O. Arulogun ◽  
Hock-Lai Choong ◽  
Debbie Taylor ◽  
Paula Ambrosoli ◽  
Graham Magor ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Myeloproliferative Neoplasm

scholarly journals SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

2017 ◽  
Author(s):  
Shengqing Gu ◽  
Azin Sayad ◽  
Gordon Chan ◽  
Wentian Yang ◽  
Zhibin Lu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Loss Of Function ◽  
Hematologic Neoplasms ◽  
Sh2 Domains ◽  
Lymphoid Neoplasia

AbstractBCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia.Ptpn11deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+pre-B cells, but is only required for the proliferation of BCR-ABL1+cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, repressesMXD3/4to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

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