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BIOMARKER:

DDX41 mutation

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Other names: DDX41, DEAD-Box Helicase 41, ABS, DEAD (Asp-Glu-Ala-Asp) Box Polypeptide 41, Probable ATP-Dependent RNA Helicase DDX41, DEAD Box Protein Abstrakt Homolog, DEAD Box Protein 41, Abstrakt, MGC8828, DEAD-Box Protein Abstrakt, Putative RNA Helicase, MPLPF
Entrez ID:
6d
Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation. (PubMed, Leukemia)
Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.
Journal
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DDX41 (DEAD-Box Helicase 41) • YTHDC1 (YTH Domain Containing 1) • METTL14 (Methyltransferase 14) • METTL3 (Methyltransferase Like 3)
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DDX41 mutation
1m
DDX41: exploring the roles of a versatile helicase. (PubMed, Biochem Soc Trans)
In this review, we will summarize the latest understandings regarding the various roles of DDX41, as well as highlight challenges associated with drug development to target DDX41. Overall, understanding the molecular and cellular mechanisms of DDX41 could help develop novel therapeutic options for DDX41 mutation-related hematologic malignancies.
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
4ms
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
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lenalidomide • azacitidine
4ms
CASE REPORT: NGS-BASED DONOR SEARCH FOR AML/MDS PATIENTS WITH DDX41 MUTATION (SIE 2023)
Treatment with DaunorubicinCytarabine was initiated, and due to the high-risk nature of the patient’s condition, a HSCT from a related donor was considered. However, no suitable donors were found, and the patient underwent a MUD 7/8 transplant. Screening family members for the same mutation when searching for a donor for HSCT can improve the chances of successful transplantation, but raises ethical and counselling considerations.This highlights the importance of reporting mutations that are classified as variants of uncertain significance (VUS) in the literature, as this can aid in identifying new pathogenic mutations in future studies The discovery of germline mutations in genes, including DDX1, that predispose individuals to hereditary hematological malignancies is crucial in allogeneic transplantation management, especially for younger and healthier patients.
Clinical • Next-generation sequencing
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SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41) • DDX1 (DEAD-Box Helicase 1)
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SRSF2 mutation • DDX41 mutation
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daunorubicin
5ms
Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients. (PubMed, Leukemia)
Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41/FLT3-ITD/TP53 (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.
Journal
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • FLT3-ITD mutation • DNMT3A mutation • ASXL1 mutation • SRSF2 mutation • DDX41 mutation
5ms
Clinical and Molecular Spectrum of Somatic Mosaic States in DDX41 mutant Germline Predisposition Syndromes (ASH 2023)
We define the somatic mosaic landscape in DDX41-MT GPS and demonstrate that somatic mutations involving the other allele, especially R525H, are seen in ~20% of pts (>80% of R525H present in MN). The frequency and composition of ARCH and myeloid driver mutations was lower than expected for the age of presentation, in comparison to de novo and secondary MDS/AML and occurred more frequently in DDX41path compared to DDX41VUS. Forty-two % (n=41), including 37% with MN, did not have somatic mosaicism, underscoring the fact that mechanisms of leukemia progression remain to be defined in subsets of affected pts.
Clinical
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TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • DNMT3A mutation • DDX41 mutation
5ms
Characteristics and Outcomes of Patients with DDX41-Mutated Acute Myeloid Leukemia: A Single-Center Experience (ASH 2023)
36% (n=13) were treated with venetoclax/hypomethylating agent (Ven/HMA) (average age 72 years) with a 69% response rate (Figure 1)... In our cohort of germline DDX41-mutated AML, responses to a 7+3- or Ven/HMA-based regimen were similar. SCT evaluation remains crucial with improved overall survival in pts receiving SCT. Our study highlights the importance of comprehensive genetic testing that includes DDX41 at diagnosis, along with testing of related donors and children of pts with a germline DDX41 mutation due to the impact of positive testing on donor selection and to identify pts at risk of AML.
Clinical
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2C (Lysine Methyltransferase 2C) • CUX1 (cut like homeobox 1) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • NPM1 mutation • ASXL1 mutation • DDX41 mutation
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Venclexta (venetoclax)
5ms
Survival and Prognosis Among 301 Patients with Newly-Diagnosed Acute Myeloid Leukemia Following Venetoclax Plus Hypomethylating Agent Therapy (ASH 2023)
Response was assessed according to the 2022 ELN criteria Patient characteristics A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 (n=100) or decitabine 20 mg/m2 days 1-5 (n=201) with Ven. In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.
Clinical
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • FLT3-ITD mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • DDX41 mutation
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Venclexta (venetoclax) • azacitidine • decitabine
6ms
LUCID: Study of Families With an Hemopathies Predisposition Related to the DDX41 Gene. (clinicaltrials.gov)
P=N/A, N=910, Recruiting, Institut Claudius Regaud | Not yet recruiting --> Recruiting
Enrollment open
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
6ms
Myeloid neoplasms with germline predisposition (PubMed, Rinsho Ketsueki)
Clonal hematopoiesis commonly occurs in healthy individuals, especially in older people. For patients with germline predisposition, clonal hematopoiesis is frequently observed at a younger age and often associated with disease-specific driver mutations, leading to further understating of the pathogenesis of diseases.
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
6ms
Clinical
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
7ms
Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients. (PubMed, Br J Haematol)
However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
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Venclexta (venetoclax)
7ms
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
7ms
Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants. (PubMed, Am J Hematol)
Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.
Clinical data • Journal
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TP53 (Tumor protein P53) • ASXL1 (ASXL Transcriptional Regulator 1) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • ASXL1 mutation • DDX41 mutation
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Venclexta (venetoclax)
7ms
New trial
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
7ms
Characteristics and Outcomes of Patients With Myelodysplastic Syndrome and DDX41 Mutation (SOHO 2023)
Among previously untreated patients, 89% received treatment, 76% of them with low-intensity therapies (LIT, including low-dose chemotherapy or hypomethylating agents), 22% with low-intensity therapies with venetoclax (LIT-Ven), and 2% with lenalidomide. Most patients with MDS with DDX41 mutations have a germline and a somatic mutation. Normal karyotype is a common finding in these patients, and, in our cohort, ASXL1 and TP53 were the most frequent co-mutations. Response rates were high, and OS was improved in patients receiving venetoclax, although not statistically significative.
Clinical
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TP53 (Tumor protein P53) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • ASXL1 mutation • SRSF2 mutation • DDX41 mutation
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Venclexta (venetoclax) • lenalidomide
7ms
Characteristics and Outcomes of Patients With Acute Myeloid Leukemia and DDX41 Mutation (SOHO 2023)
Most patients with DDX41 mutations have a combination of a germline and a somatic mutation. Normal karyotype is a common finding in these patients, with TP53, ASXL1 and SRSF2 common co-mutations. Patients treated with low-intensity treatments plus venetoclax have an improved survival and a lower incidence of disease relapse, and outcomes appear favorable with alloSCT.
Clinical
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TP53 (Tumor protein P53) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • ASXL1 mutation • SRSF2 mutation • DDX41 mutation
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Venclexta (venetoclax)
8ms
Prevalence and significance of DDX41 gene variants in the general population. (PubMed, Blood)
Finally, we found that higher mean red cell volume and somatic DDX41 mutations in blood DNA identify DDX41-GPV carriers at increased MDS/AML risk. Collectively, our findings give new insights into the prevalence and cognate risks associated with DDX41 variants, as well as the clonal evolution and early detection of DDX41-mutant MDS/AML.
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
9ms
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
9ms
Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia. (PubMed, Front Oncol)
Here, we expand on previous clinicopathologic findings on DDX41 mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized DDX41 alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
11ms
KMT2A::ARHGEF12 RARE FUSION ASSOCIATED WITH A NOVEL GERMLINE DDX41 VARIANT IN ACUTE MYELOID LEUKEMIA (EHA 2023)
Like described in most reported adult patients with KMT2A::ARHGEF12 fusion, complete remission could not be achieve by Daunorubicine and Cytarabine , neither with Azacytidine and Venetoclax. The patient is at present included in a clinical trial testing a KMT2A inhibitor, the Ziftomenib... We herein report a first case of AML with rare KMT2A::ARHGEF12 fusion transcript with a rare germline DDX41 variant. We highlight both the importance of multiple methods, including RNA high throughput sequencing, to discover rare KMT2A rearrangements as well as systematic research of DDX41 mutation in myeloid neoplasm. Reporting unusual and rare genetic aberrations is important in order to improve knowledge of their prognosis and treatments modalities including new clinical trials.
DNMT3A (DNA methyltransferase 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41) • ETNK1 (Ethanolamine Kinase 1)
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DNMT3A mutation • KMT2A rearrangement • MLL rearrangement • SRSF2 mutation • DDX41 mutation
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FusionPlex™ Pan-Heme panel
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Venclexta (venetoclax) • cytarabine • azacitidine • daunorubicin • ziftomenib (KO-539)
11ms
DDX41 GERMLINE VARIANTS: POPULATION PREVALENCE, SIGNIFICANCE AND LEUKEMIC EVOLUTION (EHA 2023)
We map the landscape of DDX41 germline variants in a cohort of 454792 volunteers and show that carriers are at increased risk of MDS/AML, but not other cancers (including MPN and lymphoma). We estimate variant-specific relative and absolute risks of MDS/AML and show that DDX41 -mutant differs to sporadic MDS/AML evolution, but is not linked to increased mutagenesis. We also report that DDX41 -GPV carriers have normal baseline bloodcounts, but those en route to MDS/AML often had higher MCV or harboured somatic DDX41 mutations.
Clinical
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
11ms
GENOMIC LANDSCAPE AND PROGNOSIS IN OLDER ACUTE MYELOID LEUKEMIA PATIENTS NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (EHA 2023)
Targeted sequencing of 263 genes was performed in 604 patients enrolled in the randomized, multi-center phase 3 'ASTRAL-1' trial (NCT02348489) evaluating the second-generation hypomethylating agent guadecitabine (SGI- 110) in treatment-naïve AML pts not eligible for intensive chemotherapy in comparison to a treatment choice of decitabine, azacitidine, or low-dose cytarabine. Using different modelling algorithms, our comprehensive analysis of the so far largest study in older, treatmentnaïve AML patients identified distinct trajectories of leukemia development, provided support for AML with mutated DDX41 as a new clinico-pathologic entity and a basis for the development of a risk stratification that may be applicable for the numerous older patients receiving less intensive therapies. Tumorigenesis, Age, AML, Prognostic groups
Clinical
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • SRSF2 mutation • Chr del(5q) • DDX41 mutation • Chr del(7q)
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cytarabine • azacitidine • guadecitabine (SGI-110)
11ms
Germline DDX41 Mutations : A Significant Entity Within Adult MDS/AML Patients (MDS 2023)
Hematopoietic stem cell transplantation (HSCT) seems to be challenging in DDX41MutGl patients, first for donor selection in the context of a familial predisposition, but also for the induced HSCT toxicity in this frail population. DDX41MutGl MDS and AML represent a specific and significant entity in myeloid neoplasms, larger studies are needed to establish specific guidelines regarding management and therapeutic options in these patients.
Clinical
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
11ms
POST-AZACITIDINE CLONE SIZE PREDICTS LONG-TERM OUTCOME OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND RELATED MYELOID NEOPLASMS (MDS 2023)
Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). Conclusions In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients.
Clinical
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TP53 (Tumor protein P53) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • EZH2 mutation • DDX41 mutation
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azacitidine
11ms
Germline DDX41 Mutations : Clinical Impact & Ethnic Diversity (MDS 2023)
DDX41 mut MNs have distinct genetic and clinical/hematological features, representing a unique subset of MNs. IPSS-R/IPSS-M prognostication may not be applied to DDX41 mut MDS.
Clinical
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TP53 (Tumor protein P53) • CUX1 (cut like homeobox 1) • DDX41 (DEAD-Box Helicase 41) • DDX3X (DEAD-Box Helicase 3 X-Linked)
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TP53 mutation • DDX41 mutation • CUX1 mutation
11ms
Enrollment open
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RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • ANKRD26 (Ankyrin Repeat Domain Containing 26)
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RUNX1 mutation • DDX41 mutation • GATA2 mutation • ETV6 mutation
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decitabine • Neupogen (filgrastim)
12ms
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation
12ms
New P2 trial
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RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • ANKRD26 (Ankyrin Repeat Domain Containing 26)
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RUNX1 mutation • DDX41 mutation • GATA2 mutation • ETV6 mutation
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decitabine • Neupogen (filgrastim)
12ms
Post-azacitidine clone size predicts outcome of patients with myelodysplastic syndromes and related myeloid neoplasms. (PubMed, Blood Adv)
Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients.
Journal
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TP53 (Tumor protein P53) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • EZH2 mutation • DDX41 mutation
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azacitidine
1year
Ribosome profiling analysis reveals the roles of DDX41 in translational regulation. (PubMed, Int J Hematol)
In addition, we found that transcripts with 5'-terminal oligopyrimidine motifs tended to be translationally upregulated when the DDX41 level was low. Our data suggest that a translationally regulated feedback mechanism involving DDX41 may exist for ribosome biogenesis.
Journal
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DDX41 (DEAD-Box Helicase 41)
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DDX41 mutation