Index case of acute myeloid leukemia in a family harboring a novel CEBPA germ line mutation.
Ontology highlight
ABSTRACT:
SUBMITTER: Ram J
PROVIDER: S-EPMC5728456 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Index case of acute myeloid leukemia in a family harboring a novel <i>CEBPA</i> germ line mutation.
Ram Jodi J Flamm Gabrielle G Balys Marlene M Sivagnanalingam Umayal U Rothberg Paul G PG Iqbal Anwar A Myers Jason R JR Corbett Anthony A Ashton John M JM Mendler Jason H JH
Blood advances 20170314 8
The persistence of a <i>CEBPA</i> mutation at the time of complete remission warrants germ line analysis.Not all patients harboring germ line <i>CEBPA</i> mutations have a family history of AML. ...[more]
Similar Datasets
Project description:BackgroundFamilial cases of adult acute myeloid leukemia (AML) with germline-mutated CCAAT/enhancer-binding protein-α (CEBPA) gene are a rare entity classified in World Health Organization (WHO) classification 2016. Most families reported in the literature show an autosomal dominant inheritance pattern consistent with a single-gene mutation.MethodsHere we studied a Syrian family with four individuals suffering from AML for CEBPA gene mutations by Sanger sequencing.ResultsThe father, his three affected, and one yet unaffected child had the same mutation in the N-terminal region of CEBPA (c.198dupC), resulting in termination at Tyr67Leufs*41. All affected family members had a good primary response to chemotherapy and achieved complete remission.ConclusionOverall, another AML family with CEBPA gene mutation is added to the literature, presenting with yet unreported FAB subtype M5 and absence of CD7 expression in some family members.
| S-EPMC8830806 | biostudies-literature
Project description:Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.
| S-EPMC8753195 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a rapidly progressing heterogeneous disease with a high mortality rate, which is characterized by hyperproliferation of atypical immature myeloid cells. The number of AML patients is expected to increase in the near future, due to the old-age-associated nature of AML and increased longevity in the human population. RUNX1 and CEBPA, key transcription factors (TFs) of hematopoiesis, are frequently and independently mutated in AML. RUNX1 and CEBPA can bind TET2 demethylase and attract it to their binding sites (TFBS) in cell lines, leading to DNA demethylation of the regions nearby. Since TET2 does not have a DNA-binding domain, TFs are crucial for its guidance to target genomic locations. In this paper, we show that RUNX1 and CEBPA mutations in AML patients affect the methylation of important regulatory sites that resulted in the silencing of several RUNX1 and CEBPA target genes, most likely in a TET2-dependent manner. We demonstrated that hypermethylation of TFBS in AML cells with RUNX1 mutations was associated with resistance to anticancer chemotherapy. Demethylation therapy restored expression of the RUNX1 target gene, BIK, and increased sensitivity of AML cells to chemotherapy. If our results are confirmed, mutations in RUNX1 could be an indication for prescribing the combination of cytotoxic and demethylation therapies.
| S-EPMC9569612 | biostudies-literature
Project description:Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.
| S-EPMC6884457 | biostudies-literature
Project description:Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.
| S-EPMC4661171 | biostudies-literature
Project description:The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells. AKI603 inhibited cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation. Surprisingly, inhibition of AurA by AKI603 induced leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells. Furthermore, the induction of senescence was associated with enhancing reactive oxygen species (ROS) level. Moreover, the anti-tumor effect of AKI603 was proved in the BALB/c nude mice KBM5-T315I xenograft model. Taken together, our data demonstrate that the small molecule AurA inhibitor AKI603 may be used to overcome drug resistance induced by BCR-ABL-T315I mutation in CML.
| S-EPMC5099696 | biostudies-other
Project description:Adult acute myeloid leukemia (AML) patients with biallelic mutations of CEBPA (biCEBPA) displays a favorable clinical outcome, and is defined as a unique entity in the 2016 World Health Organization classification. However, due to the intrinsic characteristics of the mutation, existence of co-occurring mutations and diversified gene expression signature, the prognosis of these patients needs to be analyzed in a more systematic way. In this study we evaluated the genetic characteristics and clinical outcome in a cohort of 137 biCEBPA AML cases, and proposed a prognostic nomogram to predict the overall survival (OS) of based on the clinical variables selected by multivariate Cox regression model in training cohort, including age, white blood cell count, co-existence of DNMT3A and CSF3R mutation and whether patients could achieve complete remission after induction therapy. The area under the receiver operating characteristic (ROC) curves for 3 and 5-year OS were 0.833 and 0.863, respectively. RNA sequencing of 4 relapsed patients showed that over-expression of VMP1 was an indicator of poor prognosis of biCEBPA AML patients. In conclusion, this prognostic nomogram might provide a more accurate prediction of the clinical outcomes of biCEBPA AML patients.
| S-EPMC8427751 | biostudies-literature
Project description: Not available
| S-EPMC5915999 | biostudies-literature
Project description:Germ line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.
| S-EPMC10561046 | biostudies-literature
Project description: Not available
| S-EPMC11004125 | biostudies-literature