Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFbeta-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBF beta-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBF beta-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbF beta-SMMHC.
 ...
PMID:Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. 1558 52

Acute myeloid leukaemia (AML) has been proposed to arise from the collaboration between two classes of mutation, a class I, or proliferative, mutation and a class II, or blocking, mutation. A limitation of this so-called 'two-hit' hypothesis has been the lack of identifiable proliferative and blocking mutations in most AML cases. However, it is now known that the CBFbeta-MYH11 fusion gene in AML and inv(16), by disrupting the normal transcription factor activity of core binding factor (CBF), functions as a class II mutation. In addition, nearly 70% of patients with AML and inv(16) are known to possess mutually exclusive mutations of the receptor tyrosine kinases (RTKs), c-KIT and FLT3, as well as RAS genes, that provide a class I, or proliferative, signal. AML and inv(16), therefore, is one of the best understood of the acute leukaemias at the genetic level and so provides a paradigm for the 'two-hit' hypothesis of leukaemogenesis. This paper reviews the recent advances in the molecular pathology of AML and inv(16) and discusses possible therapeutic implications of the current pathogenetic model.
 ...
PMID:Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis? 1560 46

CEBPalpha: mutations have been described in adult acute myeloid leukemia (AML) and conferred a favorable prognosis. However, CEBPalpha mutation has not been reported in children. We investigated 117 children with de novo AML using DNA PCR assay followed by sequencing for each PCR product. CEBPalpha mutations were detected in seven patients, four had FAB M2, two M1 and one M4. CEBPalpha mutations only occurred in patients with intermediate cytogenetics and not in 56 children with AML1-ETO, CBFbeta-MYH11, PML-RARalpha or MLL rearrangements. Five patients had mutations occurred in both N-terminal part and basic-leucine zipper (bZIP) domain, one had an N-terminal frameshift mutation and the remaining one had an inframe insertion in the bZIP domain. Cloning analysis on five samples carrying more than one mutations demonstrated one homozygous combined mutations and four heterozygous biallelic mutations. Four of seven CEBPalpha mutation(+) patients had cooperating mutations with FLT3-ITD or N-ras mutations compared to 27 in 109 CEBPalpha mutation(-) patients. Our results showed that CEBPalpha mutations occurred in 6% of childhood AML and most exhibited combined mutations in both N-terminal part and bZIP domain.
 ...
PMID:CEBPalpha mutations in childhood acute myeloid leukemia. 1561 61

Bone marrow samples from 43 adult patients with de novo diagnosed acute myeloid leukemia (AML)--10 acute promyelocytic leukemias (APL) with t(15;17), four AML with inv(16), seven monocytic leukemias and 22 nonmonocytic leukemias--were analyzed using high-density oligonucleotide microarrays. Hierarchical clustering analysis segregated APL, AML with inv(16), monocytic leukemias and the remaining AML into separate groups. A set of only 21 genes was able to assign AML to one of these three classes: APL, inv(16) and other AML subtype without a specific translocation. Quantitative RT-PCR performed for 18 out of these predictor genes confirmed microarray results. APL expressed high levels of FGF13 and FGFR1 as well as two potent angiogenic factors, HGF and VEGF. AML with inv(16) showed an upregulation of MYH11 and a downregulation of a gene encoding a core-binding factor protein, RUNX3. Genes involved in cell adhesion represented the most altered functional category in monocytic leukemias. Two major groups emerged from the remaining 22 AML: cluster A with 10 samples and cluster B with 12. All the eight leukemias that were either refractory to treatment or that relapsed afterwards were assigned to cluster B. In the latter cluster, CD34 upregulation and serine proteases downregulation is consistent with a maturation arrest and lack of granulocytic differentiation.
 ...
PMID:Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. 1567 61

A balanced translocation t(12;16)(p13;p13) in a patient with AML-M1 and bone marrow eosinophilia was previously analysed by FISH. The 16p13 breakpoint was shown to occur in the MYH11 gene, the fusion partner of CBFbeta in leukaemia patients with an inv(16) or a t(16;16), whereas the 12p13 breakpoint was shown to be present in cosmid c4H9. We present the molecular analysis of c4H9, resulting in the identification of a novel gene, SLAG. At the N-terminus, SLAG contains a Sec7 domain also found in proteins of the cytohesin family. In contrast to the cytohesins, no pleckstrin homology domain is present in SLAG. database searches identified several homologues, suggesting that SLAG defines a new subfamily of Sec7 proteins, characterised by an N-terminal Sec7 domain and a new C-terminal pleckstrin homology-like domain. The FISH data led to the hypothesis that rearrangement of SLAG might be involved in the pathogenesis of AML through the generation of a new fusion gene with MYH11. However, the putative SLAG-MYH11 fusions showed only weak transforming properties in NIH3T3 cells in a focus formation assay.
 ...
PMID:The der(12)t(12;16) breakpoint in an acute leukaemia case targets a Sec7 domain containing protein. 1575 9

We compared the incidence of submicroscopic deletions accompanying balanced translocations using interphase fluorescence in situ hybridization (FISH) in 245 patients with chronic myeloid leukemia (CML), 79 patients with acute lymphoblastic leukemia (ALL) and BCR-ABL (n=70) or MLL rearrangements (n=29), and 412 patients with acute myeloid leukemia (AML) with CBFB-MYH11 (n=122), PML-RARalpha (n=108), AML1-ETO (n=112), or MLL rearrangements (n=98). The incidence of submicroscopic deletions was 2-9% depending on the entity.
 ...
PMID:The incidence of submicroscopic deletions in reciprocal translocations is similar in acute myeloid leukemia, BCR-ABL positive acute lymphoblastic leukemia, and chronic myeloid leukemia. 1582 Sep 57

The pericentric inversion of chromosome 16, inv(16)(p13q22), is associated with acute myeloid leukemia (AML) subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This rearrangement fuses the CBFB and MYH11 genes, with the latter encoding the smooth muscle myosin heavy chain (SMMHC). The myeloid transcription factor CCAAT/enhancer-binding protein alpha (CEBPA) is crucial for normal granulopoiesis. Alterations of structure and expression of CEBPA have been implicated in particular subtypes of AML. Here, we found that conditional expression of core-binding factor beta (CBFB)-SMMHC in U937 cells suppresses CEBPA protein expression and binding activity. However, CEBPA mRNA levels remained unchanged. No differences were detected in CEBPA mRNA levels in patients with inv(16) AML-M4Eo (n = 12) compared to patients with AML with a normal karyotype and M4 subtype (n = 6), whereas CEBPA protein and binding activity were significantly reduced in patients with CBFB-SMMHC. Furthermore, calreticulin, an inhibitor of CEBPA translation, was induced on mRNA and protein level in CBFB-SMMHC patients with AML and after expression of CBFB-SMMHC in the U937-cell system. Inhibition of calreticulin by siRNA restored CEBPA levels. Our results suggest that modulation of CEBPA by calreticulin represents a novel mechanism involved in the differentiation block in CBFB-SMMHC AML.
 ...
PMID:CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). 1585 81

Urokinase-type plasminogen activator (uPA) is a multifunctional extracellular serine protease implicated in different events including fibrinolysis, tissue remodeling, and hematopoiesis. The human uPA gene contains a major promoter region at around 2000 bp upstream from the transcription start site (+1), and a second regulatory region spanning nucleotides -90/+32 within the proximal promoter. Here, an inspection of this region revealed a novel 13-bp palindrome residing at position +8/+20. Interestingly, the palindrome contains the DNA consensus-binding hexamer for the RUNX/AML family of transcription factors that play a role in hematopoiesis, leukemia, and several developmental processes. Measuring the expression for promoter-reporter constructs after transfection revealed that deletion of the palindrome abrogated most of the proximal promoter activity in 293A cell. Additionally, electrophoretic mobility shift assays have shown that the palindrome could bind the RUNX1 component in nuclear extracts of myeloid cell lines exclusively through its RUNX motif. The palindrome was found in five additional human genes, two of which (MYH11 and MLLT1) have been linked to chromosomal rearrangements leading to leukemia. The data presented here have implicated, for the first time, RUNX/AML in the regulation of the uPA gene. The significance of the novel palindrome regarding gene regulation through the RUNX motif deserves further investigation.
 ...
PMID:A RUNX/AML-binding motif residing in a novel 13-bp DNA palindrome may determine the expression of the proximal promoter of the human uPA gene. 1610 12

The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML) and creates a chimeric fusion protein consisting of most of the runt-related X1 co-factor, core binding factor beta fused to the smooth muscle myosin heavy chain MYH11. Expression of the ARF tumor suppressor is regulated by runt-related X1, suggesting that the inv(16) fusion protein (IFP) may repress ARF expression. We established a murine bone marrow transplant model of the inv(16) in which wild type, Arf+/-, and Arf-/- bone marrow were engineered to express the IFP. IFP expression was sufficient to induce a myelomonocytic AML even when expressed in wild type bone marrow, yet removal of only a single allele of Arf greatly accelerated the disease, indicating that Arf is haploinsufficient for the induction of AML in the presence of the inv(16).
 ...
PMID:The inv(16) cooperates with ARF haploinsufficiency to induce acute myeloid leukemia. 1619 29

Blast phase (BP) in chronic myelogenous leukemia (CML) frequently is accompanied by cytogenetic abnormalities in addition to t(9;22)(q34;q11.2). We describe 5 patients with CML in blast phase (CML-BP) in which t(9;22) and inv(16)(p13q22) were identified by conventional cytogenetics, with confirmation of BCR-ABL and CBFss-MYH11 by fluorescence in situ hybridization. The morphologic findings at the time of BP resembled de novo acute myeloid leukemia (AML) carrying inv(16)(p13q22), with abnormal eosinophils in the bone marrow and monocytosis in the peripheral blood in all cases. In 1 patient, inv(16)(p13q22) and abnormal eosinophils were detected in the bone marrow 2 months before CML-BP. The clinical course of these patients was similar to patients with CML-BP without evidence of inv(16)(p13q22). These cases illustrate that inv(16)(p13q22) is a form of cytogenetic evolution that rarely occurs in patients with CML at the time of BP. In this setting, unlike de novo AML, inv(16)(p13q22) in CML-BP is not associated with a favorable prognosis.
 ...
PMID:inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases. 1620 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>