117 Improved Growth Performance in the F1 Heterozygous Generation of an SSTR2 Knockout Model in Swine

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 36-36
Author(s):  
R Blythe Schultz ◽  
Malavika K Adur ◽  
Yunsheng Li ◽  
Zoe E Kiefer ◽  
Nicholas K Gabler ◽  
...  
Keyword(s):  
Growth Performance ◽  
Anterior Pituitary ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
The Other ◽  
Single Amino Acid ◽  
Compound Heterozygous ◽  
Production Traits ◽  
State University ◽  
Negative Effect

Abstract Targeted genetic alteration provides opportunities for rapid genetic improvement in resilience, welfare and production traits. Somatostatin (SST) acts via negative feedback to regulate growth hormone (GH) activity by antagonizing GH releasing hormone via SST receptors (SSTR) located in the anterior pituitary. Our objective was to reduce the negative effect of SST in the anterior pituitary on protein accretion by reducing the number of functional copies of SSTR2 using the CRISPR/Cas9 system. We hypothesized that a reduction or elimination of SSTR2 would lead to improved growth performance. To test this hypothesis, three commercial gilts were bred with semen from a founder boar in a compound heterozygous state at the SSTR2 locus with a 1bp deletion in one allele resulting in a premature stop codon and a 3bp deletion in the other allele resulting in the loss of a single amino acid predicted to remain functional after translation. Three litters of F1 offspring were produced (n = 46) and all piglets were confirmed to be heterozygous at the SSTR2 locus with one wild type allele and the other possessing either the 1bp deletion (n = 22) or the 3bp (n = 2 4) deletion. No differences (P > 0.43; n=46) in body weight (1.27±0.03 kg) across comparisons were observed at birth. At weaning (n = 36), males (6.19±0.20 kg) were heavier (P = 0.007) than females (5.41±0.19 kg), and piglets possessing a 1bp deletion (6.00±0.20 kg) were numerically heavier (P = 0.14) than 3bp deletion pigs (5.59±0.18 kg). This observation was more pronounced in males at weaning, where the males with the 1bp deletion were 13% heavier (P = 0.058) than those with the 3bp deletion. These data suggest that altering SSTR2 may be a viable genetic advancement strategy to improve growth performance in pigs. This project was supported by the Lloyd L. Anderson Professorship in Physiology at Iowa State University.

scholarly journals Effects of immunocastration on growth performance, body composition, meat quality, and boar taint

2017 ◽  
Vol 62 (No. 6) ◽  
pp. 249-258
Author(s):  
R. Stupka ◽  
J. Čítek ◽  
K. Vehovský ◽  
K. Zadinová ◽  
M. Okrouhlá ◽  
...  
Keyword(s):  
Growth Performance ◽  
Meat Quality ◽  
Average Daily Gain ◽  
Carcass Composition ◽  
The Other ◽  
Boar Taint ◽  
Large White ◽  
Study Objective ◽  
Negative Effect ◽  
Daily Gain

The study objective was to evaluate the effect of immunocastration in the period between the first and second vaccinations and subsequently between the second vaccination and slaughter on growth performance, carcass composition, meat quality, and boar taint, and compare results in immunocastrated males (IC), uncastrated boars (UCM), surgically castrated barrows (CM), and gilts (FE). The study included 70 pigs of the Duroc × (Large White × Landrace) crossbreed. Upon the overall assessment of the selected fattening indicators (average daily gain, feed intake), significant differences between CM and the other groups were demonstrated. Meanwhile, no significant differences were found between the IC, UCM, and FE groups. In this test, immunocastrates showed no negative effect from the second vaccination in relation to those carcass value indicators evaluated in comparison with UCM and FE. CM showed adversely lower carcass value parameters compared the other groups. No significant differences in pH, meat colour, drip loss, shear force, and intramuscular fat were found. The values of these indicators obtained for IC converged with those measured in UCM and FE. It was demonstrated that immunocastration prevented the occurrence of undesired boar taint. Androstenone decreased by 77% and skatole by 71% in IC as compared to UCM.

scholarly journals Spontaneous Loss of Virulence in Natural Populations of Listeria monocytogenes

2017 ◽  
Vol 85 (11) ◽  
Author(s):  
Mylène M. Maury ◽  
Viviane Chenal-Francisque ◽  
Hélène Bracq-Dieye ◽  
Lei Han ◽  
Alexandre Leclercq ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Host Cells ◽  
Single Amino Acid ◽  
Listeriolysin O ◽  
Loss Of Function ◽  
Phenotypic Marker ◽  
Content Type ◽  
Virulence Attenuation

ABSTRACT The pathogenesis of Listeria monocytogenes depends on the ability of this bacterium to escape from the phagosome of the host cells via the action of the pore-forming toxin listeriolysin O (LLO). Expression of the LLO-encoding gene (hly) requires the transcriptional activator PrfA, and both hly and prfA genes are essential for L. monocytogenes virulence. Here, we used the hemolytic activity of LLO as a phenotypic marker to screen for spontaneous virulence-attenuating mutations in L. monocytogenes. Sixty nonhemolytic isolates were identified among a collection of 57,820 confirmed L. monocytogenes strains isolated from a variety of sources (0.1%). In most cases (56/60; 93.3%), the nonhemolytic phenotype resulted from nonsense, missense, or frameshift mutations in prfA. Five strains carried hly mutations leading to a single amino acid substitution (G299V) or a premature stop codon causing strong virulence attenuation in mice. In one strain, both hly and gshF (encoding a glutathione synthase required for full PrfA activity) were missing due to genomic rearrangements likely caused by a transposable element. The PrfA/LLO loss-of-function (PrfA−/LLO−) mutants belonged to phylogenetically diverse clades of L. monocytogenes, and most were identified among nonclinical strains (57/60). Consistent with the rare occurrence of loss-of-virulence mutations, we show that prfA and hly are under purifying selection. Although occurring at a low frequency, PrfA−/LLO− mutational events in L. monocytogenes lead to niche restriction and open an evolutionary path for obligate saprophytism in this facultative intracellular pathogen.

LAMB GROWTH PERFORMANCE OF CERTAIN PURE BREEDS AND THEIR 2-, 3-, and 4-BREED CROSSES

1979 ◽  
Vol 59 (2) ◽  
pp. 349-357 ◽  
Author(s):  
J. A. VESELY ◽  
H. F. PETERS
Keyword(s):  
Growth Performance ◽  
Least Squares ◽  
The Other ◽  
Mating Types ◽  
Production Traits ◽  
Genetic Makeup ◽  
Breed Crosses ◽  
Lamb Growth ◽  
Better Than ◽  
Birth Type

Weaning weight, post-weaning gain, and final market weight were studied on 1734 lambs from Romnelet, Columbia, Suffolk, and North Country Cheviot breeds of sheep and their 2-, 3-, and 4-breed crosses. Several least-squares models were used; all included factors for year, age of dam, sex, birth type, and regression of the trait on age of lamb, and differed in the classification according to the genetic makeup of the lambs. Weaning weights of the purebred, and 2- and 3-breed cross lambs were significantly different (24.4, 25.6, 26.6 kg, respectively). Post-weaning gains of the three mating types were also significantly different but in a different ascending order, 19.4 kg for purebreds, 19.9 kg for 3-breed crosses, and 20.6 kg for 2-breed cross lambs. Final market weights of the purebred, and 2- and 3-breed cross lambs were 43.7, 46.3, and 46.4 kg. Means of the three traits from 3-breed cross lambs were similar to those from 4-breed cross lambs. Lambs sired by 2-breed cross rams did not perform on the average better than the lambs sired by purebred rams. Purebred Suffolk rams sired lambs that were markedly better in the production traits than those sired by the other three pure breeds and were equal to or better than those sired by crossbred rams. Only Suffolk × North Country Cheviot rams sired lambs that outperformed the lambs sired by the Suffolk rams but the differences were small.

scholarly journals Analbuminemia Produced by a Novel Splicing Mutation

2007 ◽  
Vol 53 (8) ◽  
pp. 1549-1552 ◽  
Author(s):  
Lorenzo Dolcini ◽  
Gianluca Caridi ◽  
Monica Dagnino ◽  
Alberto Sala ◽  
Selim Gökçe ◽  
...  
Keyword(s):  
Stop Codon ◽  
Direct Sequencing ◽  
Consensus Sequence ◽  
Premature Stop Codon ◽  
Autosomal Recessive Disorder ◽  
Single Strand Conformation Polymorphism ◽  
Heteroduplex Analysis ◽  
Compound Heterozygous ◽  
Albumin Concentration ◽  
Albumin Gene

Abstract Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating human serum albumin in homozygous or compound heterozygous individuals. It is an allelic heterogeneous defect, caused by a variety of mutations within the albumin gene. The analbuminemic condition was diagnosed in a Turkish female infant on the basis of low albumin concentration (∼9.0 g/L). The albumin gene was screened by single-strand conformation polymorphism and heteroduplex analysis and submitted to direct sequencing. The proband was found to be homozygous for a T→C transition at nucleotide 13381, the 2nd base of intron 11. The effect of this previously unreported mutation, which inactivates the strongly conserved GT dinucleotide at the 5′ splice site consensus sequence of intron 11, was evaluated by examining the cDNA obtained by reverse transcription-PCR from the albumin mRNA extracted from the proband leukocytes. This analysis revealed that the mutation, named Bartin for the geographical origin of the patient’s family, results in the skipping of exon 11. The subsequent frameshift within exon 12 originates a premature stop codon located 5 codons downstream at position 411. The predicted translation product would consist of 410 amino acids. This novel extensive cDNA alteration is responsible for the analbuminemic trait.

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura

2014 ◽  
Vol 34 (03) ◽  
pp. 244-248 ◽  
Author(s):  
J. A. Hovinga ◽  
K. Lackner ◽  
H.-G. Füllemann ◽  
B. Lämmle ◽  
I. Scharrer ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Late Onset ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Compound Heterozygous ◽  
Thrombocytopenic Purpura ◽  
Exon 2 ◽  
Acid Therapy ◽  
Gestational Week ◽  
Adamts13 Deficiency

SummaryWe report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

scholarly journals A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

2018 ◽  
Author(s):  
David C. Gershlick ◽  
Morié Ishida ◽  
Julie R. Jones ◽  
Allison Bellomo ◽  
Juan S. Bonifacino ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Genetic Locus ◽  
Neurodevelopmental Disorder ◽  
Failure To Thrive ◽  
The Other ◽  
Single Amino Acid ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Acid Hydrolases ◽  
Gene Encoding

AbstractGARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a six-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino-acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully-assembled GARP and EARP complexes. Likely because of this deficiency, the patient’s fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient’s fibroblasts exhibit swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.

scholarly journals Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Martina Doubková ◽  
Jakub Trizuljak ◽  
Zuzana Vrzalová ◽  
Anna Hrazdirová ◽  
Ivona Blaháková ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Clinical Manifestation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Oculocutaneous Albinism ◽  
Differential Diagnostics ◽  
Compound Heterozygous ◽  
Carrier Status ◽  
Whole Exome ◽  
Hermansky Pudlak Syndrome

Abstract Background Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. Case presentation A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. Conclusions Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

scholarly journals A Novel Adrenocorticotropin Receptor Mutation Alters Its Structure and Function, Causing Familial Glucocorticoid Deficiency

2008 ◽  
Vol 93 (8) ◽  
pp. 3097-3105 ◽  
Author(s):  
Rocío A. Artigas ◽  
Angel Gonzalez ◽  
Erick Riquelme ◽  
Cristian A. Carvajal ◽  
Andreína Cattani ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Clinical Case ◽  
Stop Codon ◽  
Transmembrane Helix ◽  
Premature Stop Codon ◽  
Autosomal Recessive Disorder ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Dynamic Simulations ◽  
Glucocorticoid Deficiency

Abstract Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by unresponsiveness to ACTH. In this study, two mutations of the ACTH receptor (MC2R) gene are reported in this FGD clinical case. Objective: The objective of the study was to characterize a novel MC2R gene mutation in a compound heterozygous patient with FGD phenotype. Design: This was a clinical case description, biochemical, molecular, and bioinformatics analysis to describe a novel MC2R gene mutation. Patients: The subject of the study was a male diagnosed with primary adrenal insufficiency. The family history showed nonconsanguineous healthy parents, three healthy siblings, and one brother affected with FGD. Main Outcome Measures: The mutant MC2R-Ala126Ser showed significantly lower activity when it was stimulated with ACTH-(1–24) than did cells transfected with wild-type MC2R. Results: The molecular studies demonstrated the presence of an adenine heterozygous insertion (InsA1347) in the MC2R gene (G217fs) in the patient. This insertion was due to a frame shift mutation in one allele and a premature stop codon codifying an aberrant receptor of 247 residues (27.2 kDa). We also found a novel heterozygous mutation alanine 126 by serine. Molecular dynamic simulations showed that serine 126 side chain fluctuates forming a noncanonical intrahelical hydrogen bond in the transmembrane helix 3 of the mutated receptor. This produces a structural rearrangement of the MC2R internal cavities that may affect the ligand recognition and signal transduction throughout the G protein. Conclusions: We propose a molecular explanation for the reduced activity exhibited by the MC2R alanine 126 by serine mutant.

scholarly journals Single nucleotide replacement in the Atlantic salmon genome using CRISPR/Cas9 and asymmetrical oligonucleotide donors

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anne Hege Straume ◽  
Erik Kjærner-Semb ◽  
Kai Ove Skaftnesmo ◽  
Hilal Güralp ◽  
Simon Lillico ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Generation Time ◽  
Genetic Improvement ◽  
Selective Breeding ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Single Amino Acid ◽  
Single Nucleotide ◽  
Homology Directed Repair ◽  
New Breeding Technologies

Abstract Background New breeding technologies (NBT) using CRISPR/Cas9-induced homology directed repair (HDR) has the potential to expedite genetic improvement in aquaculture. The long generation time in Atlantic salmon makes breeding an unattractive solution to obtain homozygous mutants and improving the rates of perfect HDR in founder (F0) fish is thus required. Genome editing can represent small DNA changes down to single nucleotide replacements (SNR). This enables edits such as premature stop codons or single amino acid changes and may be used to obtain fish with traits favorable to aquaculture, e.g. disease resistance. A method for SNR has not yet been demonstrated in salmon. Results Using CRISPR/Cas9 and asymmetrical ODNs, we were able to perform precise SNR and introduce a premature stop codon in dnd in F0 salmon. Deep sequencing demonstrated up to 59.2% efficiency in single embryos. In addition, using the same asymmetrical ODN design, we inserted a FLAG element into slc45a2 and dnd, showing high individual perfect HDR efficiencies (up to 36.7 and 32.7%, respectively). Conclusions In this work, we demonstrate that precise SNR and knock-in (KI) can be performed in F0 salmon embryos using asymmetrical oligonucleotide (ODN) donors. We suggest that HDR-induced SNR can be applied as a powerful NBT, allowing efficient introgression of favorable alleles and bypassing challenges associated with traditional selective breeding.

scholarly journals Novel AML-Associated Loss of Function Mutations in the B55 Alpha Subunit of PP2A Are Associated with Increased Phosphorylation and Activation of AKT and Enhanced Sensitivity to AKT Inhibitor Induced Cell Growth Arrest

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2206-2206 ◽  
Author(s):  
Geoffrey P. Shouse ◽  
Rosalia de Necochea-Campion ◽  
Saied Mirshahidi ◽  
Xuan Liu ◽  
Chien-Shing Chen
Keyword(s):  
Targeted Therapy ◽  
Protein Expression ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
The Other ◽  
Loss Of Function ◽  
Akt Inhibitor ◽  
Npm1 Mutation ◽  
Enhanced Sensitivity ◽  
Base Pair Deletion

Abstract Introduction Acute Myeloid Leukemia (AML) is a heterogeneous disease of myeloid progenitor cells where clonal expansion of these cells overwhelms the bone marrow leading to hematopoietic failure. Interest in identifying disruption in key regulatory pathways has led to potential for novel therapies. One particular cell signaling pathway, namely that of AKT (PKB), has been shown to correlate with AML prognosis. It has been shown previously that Protein Phosphatase 2A (PP2A) is responsible for the dephosphorylation of AKT at Thr 308 leading to decreased AKT activity. PP2A is a heterotrimeric complex consisting of a catalytic (C), scaffolding (A) and one of many regulatory (B) subunits. Studies have demonstrated that the regulatory subunit, B55α, is responsible for targeting the PP2A holoenzyme to AKT to dephosphorylate Thr 308 (Kuo et al, 2008). In fact, B55α expression has been shown to be inversely correlated with AML prognosis and Thr 308 phosphorylation of AKT (Ruvolo et al, 2011). Despite this fact, no studies have specifically demonstrated a mechanism whereby B55 Alpha expression is regulated in AML. In addition, although the potential exists for targeted therapy in patients through either activation of B55α-PP2A or disruption of AKT activity, the effectiveness of these therapies in AML has yet to be defined. In the following study we demonstrate novel loss of function mutations in the B55α gene identified in 3 AML patient samples out of 12 tested, and their effect on downstream cellular signaling pathways, including AKT, showing a possible mechanism by which B55α may act as a tumor suppressor in myeloid cells. Results Both genomic and cDNA were analyzed from leukophoresis samples of 12 unselected patients with known diagnosis of AML whose clinical data remained unknown to the primary investigator until sequencing results were completed. Two novel B55α mutations were identified in 3 of the patient samples. In 2 samples, the same nonsense mutation was identified which led to a premature stop codon at codon 77. Interestingly both of these patients had M1 AML with FLT3 ITD positivity and NPM1 mutation positivity as well as >90% blasts on marrow smear at presentation. The other mutation was a single base pair deletion leading to a frame shift causing a premature stop codon at codon 25. This patient had residual AML NOS after partial treatment and was negative for both FLT3 and NPM1 mutations. B55α protein expression was undetectable in these 3 samples, but present in the other non-mutant samples (Figure 1A). Another regulatory B subunit, B56γ, was unaffected in all samples. Lack of B55α expression correlated with loss of B55α-PP2A complexes and loss of PP2A-AKT interaction as well as increased levels in AKT Thr308 phosphorylation (Figure 1B). Samples containing B55α mutations demonstrated enhanced sensitivity to the AKT inhibitor MK2206 (Figure 2), a compound currently undergoing evaluation as a cancer chemotherapeutic in clinical trials (Yap et al, 2011). In addition, these samples were less sensitive to the PP2A activator FTY720 (Neviani et al, 2007). Conclusion Novel AML-associated mutations were identified in the B55α subunit of PP2A. The mutations led to loss of B55α protein expression and loss of B55α specific PP2A complexes within the cell. Loss of B55α PP2A disrupted interaction between PP2A and AKT and led to increased phosphorylation of AKT at Thr 308, a residue important for AKT activation. It has been previously shown that decrease in B55α expression correlates with recurrence of AML, however here we demonstrate novel loss of function mutations within the B55α gene that have the significant consequence of activating a known oncogenic protein, AKT. These samples demonstrate enhanced sensitivity and responsiveness to AKT inhibition by MK2206 compared to cells with intact B55α protein. Taken together our data illustrate a significant pathway in leukemogenesis involving one specific subset of PP2A holoenzymes. In addition, our data suggest that the presence of B55α loss of function mutations may enhance tumor responsiveness to targeted therapy by AKT inhibition. Further studies are required to evaluate the clinical efficacy of such therapies in vivo, however the results indicate a novel molecular targeting approach for optimizing AML therapy. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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