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.

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 Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development

2015 ◽  
Vol 36 (3) ◽  
pp. 462-474 ◽  
Author(s):  
Astrid Hagelkruys ◽  
Katharina Mattes ◽  
Verena Moos ◽  
Magdalena Rennmayr ◽  
Manuela Ringbauer ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Dominant Negative ◽  
Mutant Mice ◽  
Dominant Negative Effect ◽  
Mouse Development ◽  
Histone Deacetylase 2 ◽  
Histone Hyperacetylation ◽  
Negative Effect ◽  
The Impact

The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality.

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.

In Vitro Knock-Down of Myh9 Leads to a Myh9-Related Disorder Phenotype in Human Megakaryocytes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4596-4596
Author(s):  
Yolande Chen ◽  
Siham Boukour ◽  
Monia Romdhane ◽  
Ababacar Seye ◽  
Olivier Bluteau ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myosin Ii ◽  
In Vitro Study ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Gene Encoding ◽  
Related Disorder ◽  
Normal Platelet ◽  
Negative Effect

Abstract Abstract 4596 Normal platelet production is dependent on the formation of branched long cytoplasmic extensions, called proplatelets (PPT). Mutations of the Myh9 gene (encoding for the nonmuscle myosin heavy chain IIA) result in autosomal dominant disorders, where patients develop various degrees of macrothrombocytopenia, with sometimes glomerular impairment, hearing loss and cataracts. There has been questioning as to whether the mechanism for the macrothrombocytopenia is haploinsufficiency, or a dominant negative effect of the mutated gene. We performed an in vitro study to investigate PPF from patient megakaryocytes (MK). By this approach, a decrease in PPF from patient CD34 derived MKs was observed in comparison to normal cultured MK. Surprisingly this defect of PPF observed in patients was rescued by blebbistatin, an inhibitor of class II myosin. Immunofluorescence studies performed showed that besides clusterization of GPIb in patient's platelets, no major repartition abnormalities were seen in cultured MKs derived from patient's CD34 for myosin, actin, tubulin, vWF, and Rac (except in one patient where actin and Rac formed aggregates to some extend, in a small number of MKs). In order to better understand the role of myosin during normal and abnormal PPF, we used a shRNA strategy to disrupt the Myh9 expression during normal MK differentiation and compared shRNA-treated MKs with MKs derived from patient CD34. Megakaryocytes treated with a shRNA that knocks down the protein of about 50%, did not alter MK ploidization, but decreased in vitro PPF, as previously observed for cells issued from patients. Moreover, shRNA-treated MKs exhibited the same ultrastructural abnormalities as patient MKs. Addition of Blebbistatin to shRNA treated MKs led to an increase of PPF, suggesting that the remaining myosin II might be hyperactivated and inhibit PPF. Altogether this study strongly suggests that the thrombocytopenia of the Myh9 syndrome is essentially related to haploinsufficiency in myosin II. Disclosures: No relevant conflicts of interest to declare.

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 A Heterozygous Mutation in the Third Transmembrane Domain Causes a Dominant-Negative Effect on Signalling Capability of the MC4R

Obesity Facts ◽  
2008 ◽  
Vol 1 (3) ◽  
pp. 155-162 ◽  
Author(s):  
Patrick Tarnow ◽  
Anne Rediger ◽  
Harald Brumm ◽  
Petra Ambrugger ◽  
Eva Rettenbacher ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
The Third ◽  
Negative Effect

DNTM3A Mutations and Prognosis in Chronic Myelomonocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1988-1988
Author(s):  
Mrinal M Patnaik ◽  
Terra L. Lasho ◽  
Christy Finke ◽  
Matthew T Howard ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Gene Mutations ◽  
Chronic Myelomonocytic Leukemia ◽  
World Health ◽  
Prognostic Impact ◽  
Wild Type ◽  
The Impact ◽  
Myelomonocytic Leukemia

Abstract Background : DNMT3A mutations result in epigenetic dysregulation and impart a negative prognostic impact in acute myeloid leukemia and myelodysplastic syndromes. In chronic myelomonocytic leukemia (CMML), DNMT3A mutations are seen in 2-5% of patients. In a large Groupe Français des Myélodysplasies (GFM) study (n=312), DNMT3A mutations were seen in 2% and were not included in further survival analyses (Itzykson JCO 2013). In a prior Mayo Clinic study (n=175), DNMT3A mutations were seen in 5% (n=9) and on univariate, but not multivariate analysis (Patnaik Blood C J 2016), were associated with shortened over-all survival (OS). We carried out this study on a larger CMML cohort (n=261), with more (n=15) informative cases to assess the impact of DNMT3A mutations. Methods : 261 patients with World Health Organization (WHO)-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. The 2016 WHO diagnostic criteria were used. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations (LT) were documented. Mutational frequencies ≥4% were encountered in; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. i) DNTM3A mutated CMML: phenotypic and molecular correlates DNMT3A mutations were seen in 15 (6%) patients; 64% male with a median age of 64 years. DNMT3A amino acid substitutions included; R882H 50%, R882C 29%, R910P 7%, R598* 7% and R320* 7%. The median variant allele frequency burden was 45%. Concurrent gene mutations were detected in; TET2 43%, ASXL1 21%, SF3B1 21%, U2AF1 14%, RUNX1 14%, SETBP1 14%, NRAS 14%, SRSF2 7%, JAK2 7% and Tp53 7%. There was no difference between DNMT3A mutated and wild-type patients in terms of age and gender distribution, hemoglobin level, leukocyte, monocyte (AMC), and platelet counts, peripheral blood (PB) or BM blast content. Concurrent gene mutations were equally distributed with the exception for a higher prevalence of SF3B1 (p=0.003) and a lower prevalence of SRSF2 (p=0.004) mutations in DNMT3A mutated CMML. Four (29%) patients underwent leukemic transformation. ii) Impact on OS and leukemia-free survival (LFS): Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wild-type (median 27 months) patients (p=0.0007; HR 2.9, 95% CI 1.5-5.7; Figure 1A). Other variables of significance, in univariate analysis, included lower hemoglobin (p=0.002), higher leukocyte count (p=0.0009), higher AMC (p=0.0012), PB blast % (p=0.001), circulating immature myeloid cells (IMC, p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), and ASXL1 (p=0.01) mutations. Survival was also adversely affected by the presence of either (n=133) or both (n=3) ASXL1/DNMT3A mutations (0=0.007, Figure 1B). In multivariable analysis (MVA) excluding ASXL1 and DNMT3A mutations, hemoglobin (p=0.03), IMC (p=0.013) and AMC (p=0.02) retained significance. When ASXL1 mutations were added to the MVA, ASXL1 (p=0.01) mutations, AMC (p=0.012) and IMC (p=0.03) retained significance. Similarly, when only DNMT3A mutations were added to the MVA, DNMT3A (p=0.003) mutations, IMC (p=0.01) and AMC (p=0.02) retained significance. When both DNMT3A and ASXL1 mutations were added to the MVA, only DNMT3A (p<0.0001) and ASXL1 (p=0.004) mutations remained significant. DNMT3A mutations predicted shortened OS, independent of the ASXL1 inclusive GFM model (p<0.0001) and Mayo Molecular Model (p=0.002). DNMT3A mutations (p=0.0018), along with low hemoglobin levels (p=0.003) independently predicted for a shorter LFS. Conclusions: DNMT3A mutations are seen in ~5% of patients with CMML and impart a negative prognostic impact on both OS and LFS. This finding warrants inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Disclosures No relevant conflicts of interest to declare.

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