Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CEBPA encodes the transcription factor C/EBPalpha and is specifically up-regulated during granulocytic differentiation. The gene is mutated in approximately 20% of patients with acute myeloid leukemia (AML) FAB type M2 and occurs in the absence of the t(8;21). In much the same way as specific translocations are associated with a particular AML FAB type, the identification of non-random associations of gene mutation with karyotype or FAB type may be helpful in elucidating the molecular basis of certain forms of leukemia. To confirm these initial findings, 99 patients with AML FAB type M1 or M2 were screened for CEBPA mutations by use of a PCR-single-strand conformational polymorphism and sequencing approach. Nine CEBPA mutations were identified in eight patients. The mutations were clustered toward the COOH terminal of the protein and occurred exclusively in the intermediate cytogenetic risk group (8/64, 12.5%). Two patients with biallelic mutation, one homozygous for 1137Ins (57 bp) and another with two CEBPA mutations, 1096Ins (27 bp) and 363Ins (GGCC), were observed. There was no evidence for deletion of this region in the other six mutated samples analyzed by fluorescence in situ hybridization with a BAC clone spanning the CEBPA locus. CEBPA mutation status was not demonstrated to be of prognostic importance in this patient group, although this may reflect the selection and size of the AML population studied. In conclusion, mutation of CEBPA is a recurrent finding in AML and appears specific to the intermediate cytogenetic risk group patients.
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PMID:Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. 1266 Oct 7

Although a number of transcription factors (TFs) have been identified that play a pivotal role in the development of hematopoietic lineages, only little is known about factors that may influence development and lineage commitment of natural killer (NK) or NK-like T (NKT)-cells. Obviously to fully appreciate the NK- and NKT-cell differentiation process, it is important to identify and characterize the TFs effecting the NK- and NKT-cell lineage. Furthermore, these TFs may play a role in NK- or NKT-cell leukemias, in which the normal differentiation program is presumably disturbed. The present study analyzed the expression of the following 13 TFs: AML1, CEBPA, E2A, ETS1, GATA1, GATA2, GATA3, IKAROS, IRF1, PAX5, PU1, TBET and TCF1 in 7 malignant NK-cell lines together with 5 malignant NKT-cell lines, 5 T-cell acute lymphoblastic leukemia (ALL) cell lines including 3 gamma/delta T-cell receptor (TCR) type and 2 alpha/beta TCR type, and 3 B-cell precursor (BCP) leukemia cell lines. AML1, E2A, ETS1, IKAROS and IRF1 were found to be positive for all cell lines tested whereas GATA1 turned out to be universally negative. CEBPA, PAX5 and PU1 were negative for all cell lines tested except in the three positive BCP-cell lines. GATA2 was positive for 3/5 T-cell lines but negative for the other cell lines. GATA3 was positive for 7/7 NK-, 4/5 NKT-, 5/5 T- and 2/3 BCP-cell lines. TBET was positive for all NK- and NKT-cell lines and negative for all T- and BCP-cell lines except one BCP-cell line. In contrast to the expression of TBET, TCF1 was negative for all NK- and NKT-cell lines, being positive for 4/5 T- and 1/3 BCP-cell lines. Expression analysis of TFs revealed that NK- and NKT-cell lines showed identical profiles, clearly distinct from those of the other T-ALL or BCP-ALL leukemia-derived cell lines..
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PMID:Transcription factor expression in cell lines derived from natural killer-cell and natural killer-like T-cell leukemia-lymphoma. 1536 40

We describe a family in whom three members affected by acute myeloid leukemia (AML) had an identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha. Unaffected family members did not have this mutation. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. One of them had a second CEBPA mutation, but only at the time of diagnosis. All three patients are currently well, with no abnormalities in the bone marrow. CEBPA mutation is apparently the primary event in the development of AML in this family.
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PMID:Mutation of CEBPA in familial acute myeloid leukemia. 1557 52

Genome-wide analysis of single nucleotide polymorphisms in 64 acute myeloid leukemias has revealed that approximately 20% exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission bone marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the leukemic clone. Two examples of UPD11p were shown to be of different parental origin as indicated by the methylation pattern of the H19 gene. Furthermore, a previously identified homozygous mutation in the CEBPA gene coincided with a large-scale UPD on chromosome 19. These cryptic chromosomal abnormalities, which seem to be nonrandom, have the characteristics of somatic recombination events and may define an important new subclass of leukemia.
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PMID:Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. 1569 75

Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
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PMID:Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. 1623 Mar 71

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.
Leukemia 2005 Dec
PMID:Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. 1628 Oct 72

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.
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PMID:Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. 1922 36

Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.
Leukemia 2008 May
PMID:Cooperating gene mutations in acute myeloid leukemia: a review of the literature. 1828 31

Leukemia-initiating cells can originate from hematopoietic progenitor cells that have acquired self-renewal capacity upon transformation with leukemic fusion genes. In this issue of Cancer Cell, Kirstetter and colleagues describe a mouse model for the frequent CEBPA mutations in human acute myeloid leukemia that result in the synthesis of only the 30kDa isoform, but not the 42kDa isoform of C/EBPalpha. This mutation uncouples C/EBPalpha's roles in myeloid differentiation and proliferation control. Furthermore, this mutation activates self-renewal in committed myeloid progenitor cells and induces myeloid malignancy with complete penetrance that is sustained by leukemia-initiating cells with a committed myeloid molecular signature.
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PMID:C/EBPalpha in leukemogenesis: a matter of being in the right place with the right signals. 1839 53

Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.
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PMID:Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. 1839 49


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