scholarly journals Four novel mutations in the ALPL gene in Chinese patients with odonto, childhood, and adult hypophosphatasia

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Lijun Xu ◽  
Qianqian Pang ◽  
Yan Jiang ◽  
Ou Wang ◽  
Mei Li ◽  
...  
Keyword(s):  
Serum Alkaline Phosphatase ◽  
Gene Mutations ◽  
Dominant Negative ◽  
Chinese Patients ◽  
Dominant Negative Effect ◽  
Healthy Controls ◽  
Missense Mutations ◽  
Genetic Characteristics ◽  
Chinese Families ◽  
Negative Effect

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone and/or dental mineralization, and decreased serum alkaline phosphatase (ALP) activity. ALPL, the only gene related with HPP, encodes tissue non-specific ALP (TNSALP). Few studies were carried out in ALPL gene mutations in the Chinese population with HPP. The purpose of the present study is to elucidate the clinical and genetic characteristics of HPP in five unrelated Chinese families and two sporadic patients. Ten clinically diagnosed HPP patients from five unrelated Chinese families and two sporadic patients and fifty healthy controls were genetically investigated. All 12 exons and exon–intron boundaries of the ALPL gene were amplified by PCR and directly sequenced. The laboratory and radiological investigations were conducted simultaneously in these HPP ten patients. A 3D model of the TNSALP was used to predict the dominant negative effect of identified missense mutations. Three odonto, three childhood, and four adult types of HPP were clinically diagnosed. Ten mutations were identified in five unrelated Chinese families and two sporadic patients, including eight missense mutations and two frameshift mutations. Of which, four were novel: one frameshift mutation (p.R138Pfsx45); three missense mutations (p.C201R, p.V459A, p.C497S). No identical mutations and any other new ALPL mutations were found in unrelated 50 healthy controls. Our study demonstrated that the ALPL gene mutations are responsible for HPP in these Chinese families. These findings will be useful for clinicians to improve understanding of this heritable bone disorder.

DNM1 Gene and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Milena Motta ◽  
Maria Chiara Consentino ◽  
Alessandra Fontana ◽  
Laura Sciuto ◽  
Raffaele Falsaperla ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Wide Spectrum ◽  
Intractable Epilepsy ◽  
Gene Mutations ◽  
Infantile Spasms ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
De Novo Mutations ◽  
Negative Effect

AbstractThe phenotypic variety associated to mutations in dynamin 1 (DNM1), codifying the presynaptic protein DNM1 has been increasingly reported, mainly related to encephalopathy with intractable epilepsy; currently, it is known the phenotype related to DNM1 gene mutations is relatively homogeneous with developmental delay, hypotonia, and epilepsy characterized by infantile spasms and possible progression to Lennox-Gastaut syndrome. By examining all the papers published until 2020 (18 articles), we compared data from 30 patients (extrapolated from 5 papers) with DNM1 mutations, identifying 26 patients with de novo mutations in DNM1. Nine patients (33.3%) reported the recurrent mutation p.Arg237Trp. A usual phenotype observed comprises severe to deep developmental delay and muscular hypotonia in all patients with epilepsy beginning with infantile spasms, which often evolved into Lennox-Gastaut syndrome. Data about GTPase or central domains mutations, and existing structural modeling and functional suggest a dominant negative effect on DMN1 function. Generally genetic epilepsies consist of a wide spectrum of clinical features, unlike that, DNM1-related CNS impairment phenotype is quite uniform. In up to one third of patients it has been found variant p.Arg237Trp, which is one of the most frequent variant detected in epileptic encephalopathies. The understanding of DNM1 function opens up the chance that this gene would become a new therapeutic target for epilepsies.

scholarly journals Characterization of ANGPT2 mutations associated with primary lymphedema

2020 ◽  
Vol 12 (560) ◽  
pp. eaax8013 ◽  
Author(s):  
Veli-Matti Leppänen ◽  
Pascal Brouillard ◽  
Emilia A. Korhonen ◽  
Tuomas Sipilä ◽  
Sawan Kumar Jha ◽  
...  
Keyword(s):  
De Novo ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Missense Mutations ◽  
Activation Mechanisms ◽  
Primary Lymphedema ◽  
Negative Effect

Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain <30% of cases. Angiopoietin 1 (ANGPT1) and ANGPT2 function via the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor–like domains 1 and 2) receptor complex and α5β1 integrin to form an endothelial cell signaling pathway that is critical for blood and lymphatic vessel formation and remodeling during embryonic development, as well as for homeostasis of the mature vasculature. By screening a cohort of 543 individuals affected by primary lymphedema, we identified one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)–ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling. WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. Molecular modeling and biophysical studies showed that amino-terminally truncated ANGPT subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio. The T299M mutant, located in the dimerization interphase, showed reduced integrin α5 binding, and its expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. These results demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.

scholarly journals A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies

Science ◽  
2019 ◽  
Vol 365 (6453) ◽  
pp. 599-604 ◽  
Author(s):  
Steffen Boettcher ◽  
Peter G. Miller ◽  
Rohan Sharma ◽  
Marie McConkey ◽  
Matthew Leventhal ◽  
...  
Keyword(s):  
Dna Binding ◽  
Leukemia Cell ◽  
Dominant Negative ◽  
Single Amino Acid ◽  
Dominant Negative Effect ◽  
Human Leukemia ◽  
Missense Mutations ◽  
Myeloid Malignancies ◽  
Missense Variants ◽  
Negative Effect

TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

scholarly journals Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

2021 ◽  
Author(s):  
Ashley S. Denney ◽  
Andrew D. Weems ◽  
Michael A. McMurray
Keyword(s):  
Three Dimensional ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Temperature Sensitive ◽  
Missense Mutations ◽  
Tumor Suppressor P53 ◽  
Wild Type ◽  
Type Function ◽  
Negative Effect ◽  
Chaperone Interactions

ABSTRACTLife requires the oligomerization of individual proteins into higher-order assemblies. In order to form functional oligomers, monomers must adopt appropriate three-dimensional structures. Molecular chaperones transiently bind nascent or misfolded proteins to promote proper folding. Single missense mutations frequently cause disease by perturbing folding despite chaperone engagement. A misfolded mutant capable of oligomerizing with wild-type proteins can dominantly poison oligomer function. We previously found evidence that human-disease-linked mutations in Saccharomyces cerevisiae septin proteins slow folding and attract chaperones, resulting in a kinetic delay in oligomerization that prevents the mutant from interfering with wild-type function. Here we build upon our septin studies to develop a new approach to identifying chaperone interactions in living cells, and use it to expand our understanding of chaperone involvement, kinetic folding delays, and oligomerization in the recessive behavior of tumor-derived mutants of the tumor suppressor p53. We find evidence of increased binding of several cytosolic chaperones to a recessive, misfolding-prone mutant, p53(V272M). Similar to our septin results, chaperone overexpression inhibits the function of p53(V272M) with minimal effect on the wild type. Unlike mutant septins, p53(V272M) is not kinetically delayed under conditions in which it is functional. Instead, it interacts with wild-type p53 but this interaction is temperature sensitive. At high temperatures or upon chaperone overexpression, p53(V272M) is excluded from the nucleus and cannot function or perturb wild-type function. Chaperone inhibition liberates the mutant to enter the nucleus where it has a slight dominant-negative effect. These findings provide new insights into the effects of missense mutations.

scholarly journals Role of the novel endoribonuclease SLFN14 and its disease causing mutations in ribosomal degradation

2018 ◽  
Author(s):  
Sarah J. Fletcher ◽  
Vera P. Pisareva ◽  
Abdullah Khan ◽  
Andrew Tcherepanov ◽  
Neil V. Morgan ◽  
...  
Keyword(s):  
In Vitro Models ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
Missense Mutations ◽  
The Novel ◽  
Excessive Bleeding ◽  
Negative Effect ◽  
Inherited Thrombocytopenia

ABSTRACTPlatelets are anucleate and mostly ribosome-free cells within the bloodstream, derived from megakaryocytes within bone marrow and crucial for cessation of bleeding at sites of injury. Inherited thrombocytopenias are a group of disorders characterized by alow platelet count and are frequently associated with excessive bleeding. SLFN14 is one of the most recently discovered genes linked to inherited thrombocytopenia where several heterozygous missense mutations in SLFN14 were identified to cause defective megakaryocyte maturation and platelet dysfunction. Yet, SLFN14 was recently described as a ribosome-associated protein resulting in rRNA and ribosome-bound mRNA degradation in rabbit reticulocytes. To unveil the cellular function of SLFN14 and the link between SLFN14 and thrombocytopenia, we examined SLFN14 (WT/mutants) in in vitro models. Here, we show that all SLFN14 variants co-localize with ribosomes and mediate rRNA endonucleolytic degradation and ribosome clearance. Compare dto SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein. Moreover, all SLFN14 variants tend to form oligomers. These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in patients’ platelets. Overall we suggest that SLFN14 could be involved in ribosome degradation during platelet formation and maturation.

scholarly journals Mutant p53 Enhances the Development and Sustained Growth of MYC-Driven Lymphoma and Exerts a Dominant Negative Effect Preferentially Deregulating Pathways for Metabolism and DNA Repair

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1545-1545
Author(s):  
Brandon J Aubrey ◽  
Ana Janic ◽  
Yunshun Chen ◽  
Gordon K Smyth ◽  
Andrew J Kueh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Target Genes ◽  
Human Cancer ◽  
Gene Mutations ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Wild Type ◽  
Over Expression ◽  
Negative Effect ◽  
Induced Apoptosis

Abstract Over-expression of the c-MYC oncogene and Trp53 gene mutations are among the most common genetic alterations in human cancer and, when combined, result in highly aggressive malignant disease. Trp53 gene mutations produce over-expressed mutant TRP53 proteins that drive cancer growth through both loss of wild-type Trp53 tumor suppressor function and gain-of-function oncogenic properties. The Eμ-Myc mouse model provides a setting to study the functional interplay between c-Myc over-expression and mutant TRP53 proteins. Eμ-Myc transgenic mice carry a c-Myc transgene under the control of the immunoglobulin heavy chain gene enhancer (Eμ), recapitulating the chromosomal translocation underlying human Burkitt Lymphoma, and develop aggressive pre-B/B cell lymphoma with a high (~20%) spontaneous rate of Trp53 mutation. The effect of five mouse mutant TRP53 proteins (V170M, I192S, G280, R246Q, R270H) was initially examined in three settings (Trp53-/-, Trp53+/- and Trp53+/+;Eμ-Myc) using a hematopoietic stem and progenitor cell (HSPC) reconstitution model. Each mutant TRP53 protein studied corresponds to a commonly re-occurring Tp53 mutation in human cancer. Retroviral over-expression enabled the comparison of mutant-specific and genotype-specific features for each mutant TRP53 protein. Mutant TRP53 expression did not accelerate lymphoma development in mice receiving Trp53-/- or Trp53+/- HSPCs. However, mice reconstituted with Trp53+/- HSPCs expressing the TRP53 mutants displayed an altered tumor spectrum compared to mice reconstituted with control Trp53+/- HSPCs. In contrast, mutant TRP53 markedly accelerated lymphoma development in mice receiving Trp53+/+;Eμ-Myc HSPCs, highlighting a synergy between c-Myc over-expression and Trp53 mutations in neoplastic transformation. Furthermore, inducible mutant TRP53 expression demonstrated a dependency on sustained expression of mutant TRP53 in established MYC-driven lymphomas. Notably, none of the c-MYC plus mutant TRP53 driven lymphomas exhibited spontaneous endogenous Trp53 mutations. Despite the enhanced tumorigenesis, most established lymphomas from this model displayed sensitivity to TRP53-activating drugs consistent with a weak dominant negative effect over wild-type Trp53-induced apoptosis. Consistent with this finding, pre-malignant Trp53+/+;Eμ-Myc primary B-cells expressing mutant TRP53 were not protected against Trp53-induced apoptosis. Pre-malignant B-cells displayed a small increase in cell cycling and an expansion of the tumor-initiating pre/pro-B cell population. Most significantly, functional assessment of DNA damage in pre-malignant cells, using single cell gel electrophoresis (comet assay) and γ-H2AX staining, revealed increased DNA damage, suggesting an important role for defects in DNA repair during mutant TRP53-driven lymphoma development. To investigate the nature of the dominant negative effect, mutant TRP53 protein was exogenously expressed in mouse Eµ-Myc Trp53+/+ lymphoma cell lines. The impact of mutant TRP53 on the transcriptional function of the endogenous wild-type TRP53 protein was then studied using the TRP53-activating compound, nutlin-3a. Surprisingly, in established lymphoma cell lines, mutant TRP53 impaired nutlin-3a-induced apoptosis despite substantial induction of the critical pro-apoptotic effector, PUMA. To explore this finding further, we globally characterized the dominant negative effect, and assessed for mutant TRP53-specific transcriptional targets, by performing whole transcriptome sequence (RNAseq) analysis after treatment with nutlin-3a. Analysis of known wild-type Trp53 target genes (n=283) demonstrated that the induction of these genes as a group was repressed in the presence of the mutant TRP53 protein (ROAST test, p=6.7e-04). Remarkably, however, mutant TRP53 significantly repressed only 57% of the nutlin-3a-induced Trp53 target genes. Analysis of these strongly repressed genes highlighted the importance of several pathways, including metabolism, DNA damage repair and negative feedback loops in TRP53 signaling. This suggests a previously unrecognized selectivity of the dominant-negative-effect for certain p53 pathways that may be important in cancer initiation. Additional mutant TRP53-specific transcriptional targets were also identified and are under further investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gonadal Dysgenesis Without Adrenal Insufficiency in a 46, XY Patient Heterozygous for the Nonsense C16X Mutation: A Case of SF1 Haploinsufficiency

2004 ◽  
Vol 89 (10) ◽  
pp. 4829-4832 ◽  
Author(s):  
Delphine Mallet ◽  
Patricia Bretones ◽  
Laurence Michel-Calemard ◽  
Frederique Dijoud ◽  
Michel David ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Gonadal Dysgenesis ◽  
Gene Dosage ◽  
Gene Mutations ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Seminiferous Tubules ◽  
Heterozygous Mutation ◽  
Orphan Nuclear Receptor ◽  
Missense Mutations

Abstract Targeted disruption of the orphan nuclear receptor SF1 results in the absence of adrenals and gonads, establishing that this transcription factor is implicated in gonadal determination and adrenal development. Four human SF1 gene mutations have been described to date: three (G35E, R92Q, R255L) were responsible for adrenal insufficiency associated with a gonadal dysgenesis in two 46, XY individuals, one (8 bp deletion in exon 6) resulted in gonadal dysgenesis without adrenal insufficiency. We identified a new heterozygous SF1 gene mutation, C16X, in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation causes premature termination of translation and should abolish all SF1 activity. Therefore haploinsufficiency could explain the deleterious effect of this mutation in our patient suggesting that testis development is more SF1 dose-dependant than adrenal development. Although the same mechanism explains the deleterious effects of SF1 missense mutations, recent studies have demonstrated an additional dominant negative effect. These data suggest that heterozygous mutation impaired adrenal development only if the two mechanisms, gene dosage and dominant negative effects occur.

scholarly journals Identifying Gene Mutations in Autosomal Recessive Cerebellar Ataxias and Extending the Mutational Spectrum in China

2021 ◽  
Author(s):  
Xueping Chen ◽  
Xiaoqin Yuan ◽  
Qian-Qian Wei ◽  
RuWei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Autosomal Recessive Inheritance ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Genetic Characteristics ◽  
Targeted Next Generation Sequencing ◽  
Cerebellar Ataxias ◽  
Autosomal Recessive Cerebellar Ataxias

Abstract Background: Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous, complex, disabling neurodegenerative diseases characterized by autosomal recessive inheritance and cerebellar ataxia. Numerous mutations are described in several populations. However, in China, few data are available concerning ARCA. In this study, we aimed to identify ARCA-associated ataxia by targeted next-generation sequencing or whole-exome sequencing in a Chinese cohort, trying to determine clinical and genetic characteristics of Chinese patients with ARCA.Results: We identified 15 different mutations in 7 unrelated patients, of which 12 were novel, including seven missense mutations, three frameshift mutations, two splicing mutations, two nonsense mutations, and one inframe deletion mutation. The most frequent gene was ATM (3 patients), followed by SACS (2 patients), SYNE1 (2 patients), and SETX (1 patient). Specifically, 1 patient harbored mutations in both ATM and SYNE1. The phenotype was mainly cerebellar ataxia in all these cases. However, peripheral neuropathy, dystonia, oculomotor abnormalities, pyramidal tract dysfunction, cognitive impairment, and epilepsy were also revealed. Patients who harbored different gene mutations showed mutational heterogeneity. Conclusions: Our results indicate that ARCA-associated gene mutations are uncommon with additional clinical features in the Chinese population, and advanced sequencing is required to aid the diagnosis of undetermined cerebellar ataxia in Chinese patients.

The Impact of Different DNMT3A Mutations on Outcome in Younger Adults with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 67-67
Author(s):  
Rosemary E Gale ◽  
Katarina Lamb ◽  
Christopher Allen ◽  
Dima El-Sharkawi ◽  
Cassandra Stowe ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
Prognostic Impact ◽  
Missense Mutations ◽  
Limited Information ◽  
Negative Effect ◽  
The Impact

Abstract DNMT3A mutations (DNMT3AMUT) are recurrent in AML. They predominate in patients with intermediate-risk (IR) cytogenetics and are often co-incident with FLT3ITD and NPM1MUT. Their prognostic impact is unclear. Most reports suggest they are associated with a worse outcome, but a large study including 1060 younger adult IR patients found that DNMT3AMUT had no significant impact on survival endpoints. Variable results have also been reported for different FLT3/NPM1 subgroups. Missense mutations at R882 in exon 23 occur in ≈65% of patients, but other missense and truncation mutations occur throughout the gene, mainly in exons 13-23. There is limited information on the prognostic impact of the different mutations, although they may have differing functional consequences. We therefore screened exons 13-23 in DNA samples from 914 younger adult AML patients (median age 43 years) with IR cytogenetics treated on UK MRC trials and evaluated outcome according to type of DNMT3Amutation. Overall, 278 mutations were detected in 272 (30%) patients; 175 (64%) had R882 missense mutations, 59 (22%) other missense mutations, 35 (13%) truncations or in-frame deletions; 3 (1%) had 2 mutations of differing types. Median R882 mutant level in 172 mutated cases was 47% (range 15-85%), consistent with a heterozygous mutation in most cells. Patients with DNMT3AMUT were significantly older than those with DNMT3A wild-type (DNMT3AWT) (P<.0001), more likely to be female (P=.004), have a higher presenting WBC (P<.0001), and a normal rather than abnormal karyotype (P<.0001). The presence of DNMT3AMUT positively correlated with FLT3ITD (P=.0003) and NPM1MUT (P<.0001) and negatively correlated with CEBPAMUT (P<.0001). Patients with R882 mutations had significantly higher WBC (P=.005) and correlation with NPM1MUT (P=.01) than non-R882 mutated patients; non-R882 missense mutated patients had higher WBC (P=.05) and non-significant higher co-incidence with FLT3ITD than those with truncations. Presence of DNMT3AMUT was associated with a poorer prognosis, but this difference was only seen if the results were analyzed separately according to NPM1 genotype, where DNMT3AMUT was associated with higher cumulative incidence of relapse (CIR) than DNMT3AWT in cases with NPM1MUT (49% vs 40%, P=.01) and NPM1WT (61% vs 58%, P=.5) genotype. Similarly, DNMT3AMUT patients had worse overall survival (OS) than DNMT3AWT patients with NPM1MUT (38% vs 50%, P=.008) and NPM1WT (15% vs 25%, P=.09) genotype. This statistical anomaly is an example of Simpson’s paradox. It results from the strong co-incidence of DNMT3A and NPM1 mutations with opposing prognostic associations that mask the effect seen separately when the groups are combined. Although the differences were smaller for NPM1WT cases, tests for heterogeneity showed that the impact of a DNMT3A mutation did not differ between NPM1MUT and NPM1WT for either CIR or OS, nor between the 4 genotypes defined by the combination of NPM1 and FLT3ITD genotypes. In multivariable analysis including age, WBC, NPM1 and FLT3ITD, DNMT3AMUT was a significant adverse risk factor for CIR (HR=1.27, CI=1.01-1.61; P=.04), and showed a trend for being adverse for OS (HR=1.19, CI=.98-1.45; P=.08). When outcome was considered according to the type of mutation (R882, other missense or truncations), for the NPM1MUT genotype cases CIR was highest in R882 and other missense cases (51%, 50%) and truncation cases were similar to DNMT3AWT (35%, 40%). For NPM1WT, CIR was highest in R882 cases (76%), similar in other missense and DNMT3AWT cases (55%, 58%) and lowest in truncation cases (40%). Consistent with this data, for NPM1MUT genotype, OS was lowest in R882 and other missense cases (35%, 38%), better in DNMT3AWT (50%) and highest in truncation cases (57%). For NPM1WT, OS was lowest in R882 cases (11%), and similar in DNMT3AWT, other missense and truncation cases (25%, 21%, 18% respectively). These data suggest that screening cannot be limited to the hotspot R882 mutations and that cases with missense mutations should be treated as poor risk, including those patients currently considered as favorable risk such as NPM1MUTFLT3WT. Conversely, truncation mutations have a different functional impact from missense mutations, more likely to result in haploinsufficiency than a dominant-negative effect, and these cases should be considered as equivalent to DNMT3AWT for prognostication and selection of therapy in 1st remission. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document