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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
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PMID:Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML. 1987 71

In a recent study published in Cancer Cell, Bereshchenko and colleagues (2009) report a knockin mouse model that represents the most frequently occurring biallelic combination of CEBPA mutations found in human acute myeloid leukemia.
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PMID:Preview. Mutant CEBPA: Priming Stem Cells for Myeloid Leukemogenesis. 1989 32

C/EBPalpha plays an essential role as a transcription factor in myeloid cell differentiation. Here, we describe a Japanese family in which two individuals with acute myeloid leukemia (AML) and one healthy individual had an identical 4-base pair insertion in the N-terminal region of CEBPA (350_351insCTAC), resulting in the termination at codon 107 (I68fsX107). The father and a son at diagnosis of AML had different in-frame insertion mutations in the C-terminal region of C/EBPalpha. These C-terminal mutations disappeared upon remission in both patients. Interestingly, the father showed different in-frame insertion mutations in the C-terminal CEBPA at the time of diagnosis and relapse. These data strongly suggest that the N-terminal C/EBPalpha mutation predisposes to the occurrence of a C-terminal C/EBPalpha mutation as a secondary genetic hit, causing AML.
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PMID:A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation. 1995 36

Acute myeloid leukaemia (AML) is a complicated, heterogeneous disease and the prognostic factors may be useful in deciding upon appropriate therapy. Cytogenetic testing at diagnosis yields critical prognostic information, but more refinement in prognosis is required. Within cytogenetic subgroups, further important subgroup definitions are possible based on the mutation status and expression analysis of genes such as C-KIT, FLT3, NPM1 and CEBPA, although defining therapies based on such mutations remains controversial.
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PMID:Prognostic factors in AML in relation to (ab)normal karyotype. 1995 3

We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy.
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PMID:The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA. 1996 47

microRNA-223 (miR-223) can trigger normal granulopoiesis. miR-223 expression is regulated by two distinct CEBPA (CCAAT/enhancer binding protein-alpha) sites. Here, we report that miR-223 is largely suppressed in cells from acute myeloid leukemia (AML) patients. By sequencing, we found that miR-223 suppression in AML is not caused by DNA sequence alterations, nor is it mediated by promoter hypermethylation. The analysis of the individual contribution of both CEBPA sites to miR-223 regulation identified the site upstream of the miR-223 primary transcript as the predominant regulatory element. Our results suggest that miR-223 suppression in AML is caused by impaired miR-223 upstream factors.
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PMID:Complexity of miR-223 regulation by CEBPA in human AML. 2001 73

We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).
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PMID:DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. 2012 41

Cytogenetic aberrations have long been recognized as the most important prognostic variable in acute myeloid leukemia (AML) and are now a major stratification tool for post-remission therapy. Cytogenetics-based stratification improves survival. Patients with AML and normal cytogenetics, the largest single subgroup, have had a very heterogeneous outcome with standard chemotherapy in multiple clinical trials. Hence it is difficult to recommend a "one size fits all" kind of treatment for this heterogeneous population of AML patients. New emerging data from preclinical, retrospective, and large, randomized controlled studies indicate that in addition to cytogenetic abnormalities, many other molecular aberrations are operative in the response to treatment as well as in the risk of relapse. Such molecular markers are being tested for developing targeted therapies and may help in improved stratification of patients in the selection of post-remission therapy. Emerging evidence reveals that at the submicroscopic level, AML with normal cytogenetics may carry poor prognostic genetic lesions or "molecular signatures" as is the case with FLT3 mutations and overexpression of BAALC, ERG or MN1, or may have aberrations that predict better risk as is the case with isolated NPM1 or CEBPA mutations. Later studies have tried to explore the interaction of various prognostically important genes in this group of AML patients. The utility of the evolving data for bedside management of such patients is expected to improve with the wider application of modern tools, using the proposed clinical outcome models, and probably by development of a risk-scoring system based on the relative risk associated with each molecular aberration. The goals include identifying those patients most likely to benefit from upfront allogeneic HSCT and sparing good-prognosis patients from unnecessary transplant-related morbidity. The following is an outline of the most common molecular changes, their impact on the outcome of AML patients with normal cytogenetics and challenges in their wide scale application in risk stratification.
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PMID:The challenge of risk stratification in acute myeloid leukemia with normal karyotype. 2006 45

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). However, about 50% of newly diagnosed acute myeloid leukemia (AML) cases have normal karyotype. These patients are very heterogenous with respect to acquired gene mutations and gene expression changes. The identification of these genetic alterations may lead to improved prognostification and generation of novel risk-adapted therapies. The aim of this work was to study the prognostic impact of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha) and expression of the BAALC gene (for brain and acute leukemia, cytoplasmic), a novel gene involved in leukemia, in 38 adults with AML and normal cytogenetics. Screening for mutations of CEBPA gene was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP), and BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in blood or bone marrow samples. CEBPA mutations were found in 7 (18.4%) of 38 patients, 36.8 % (14 of 38) had low BAALC expression and 63.2 % (24 of 38) had high BAALC expression. Patients with CEBPA mutations had favorable course of their disease. They had higher rate of complete remission (CR) (85.7 % vs 51.6 %; P = 0.108), lower incidence of relapse (0% vs. 41.9%; P = 0.038). Disease free survival (DFS) and overall survival (OS) were significantly longer for patients with CEBPA mutations compared with patients without mutations (mean 13.65 +/- 5.41 vs. 7.32 +/- 4.33 months, P = 0.047; mean 15.32 +/- 6.5 vs 8.5 +/- 3.21 months, P = 0.039; respectively). Compared to low BAALC expressers, high BAALC expressers had lower incidence of CR (50% vs 71.4%; P = 0.171), higher incidence of relapse (50% vs. 14.3%; P = 0.029), and showed significantly shorter DFS (mean 7.5 +/- 2.12 vs. 11.67 +/- 4.6 months, P = 0.038) and inferior overall survival (mean 9.1 +/- 3.52 vs. 13.22 +/- 4.21 months, P = 0.024). On multivariable analysis, wild-type CEBPA as well as high BAALC expression were confirmed as independent risk factors predicting inferior DFS (CEBPA, hazard ratio 0.066, P = 0.001; BAALC, hazard ratio 3.98, P = 0.003) and inferior OS (CEBPA, hazard ratio 0.125, P = 0.002; BAALC, hazard ratio 4.215, P = 0.001). Data obtained in this study suggest that CEBPA mutation status and BAALC expression are important prognostic factors in AML patients with normal cytogenetics and their incorporation into novel risk-adapted therapeutic strategies may improve the currently disappointing cure rate of this group of patients.
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PMID:Prognostic significance of CEBPA mutations and BAALC expression in acute myeloid leukemia Egyptian patients with normal karyotype. 2030 78

The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P < .001), French-American-British M6 subtype (P = .006), and t(7;11)(p15;p15) (P = .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P < .001). Sequential analyses were performed on 133 patients. WT1 mutations disappeared at complete remission in all WT1-mutated patients studied. At relapse, 3 of the 16 WT1-mutated patients who had paired samples lost the mutation and 2 acquired additional mutations, whereas 3 of 110 WT1-wild patients acquired novel mutations. In conclusion, WT1 mutations are correlated with poor prognosis in AML patients. The mutation status may be changed in some patients during AML progression.
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PMID:WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. 2036 69


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