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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies on concordant acute lymphoblastic leukemia (ALL) in identical twins have identified the leukemia as monoclonal with MLL or ETV6-RUNX1 gene fusion as early or initiating events in utero. In the latter case, postnatal latency is associated with secondary genetic events such as ETV6 deletion. We describe here a pair of infant twins with concordant acute monoblastic leukemia (AML). They are a unique pair in that their leukemia blasts display extensive intraclonal chromosomal diversity. Comparison of the leukemic cells between the two twins by karyotype and fluorescence in situ hybridization identifies a common or shared stem line and extensive subclonal diversity for which the twins' leukemic populations are divergent. This case of leukemia illustrates in utero initiation with early imposition of chromosomal instability, the progressively divergent evolution of which can be mapped in the twins into pre- and postnatal periods.
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PMID:Prenatal chromosomal diversification of leukemia in monozygotic twins. 1280 Jan 52

AML1/RUNX1, located on chromosome band 21q22, is one of the most important hematopoietic transcription factors. AML1 is frequently affected in leukemia and myelodysplastic syndrome with 21q22 translocations. Recently, AML1 mutations were found in adult hematologic malignancies, especially acute myeloid leukemia (AML)-M0 or leukemia with acquired trisomy 21, and familial platelet disorder with a predisposition toward AML. Through the use of polymerase chain reaction-single-strand conformation polymorphism analysis, we examined the AML1 gene for mutations in 241 patients with pediatric hematologic malignancies, and we detected AML1 mutations in seven patients (2.9%). Deletion was found in one patient, and point mutations in four patients, including three missense mutations, two silent mutations, and one mutation within an intron resulting in an abnormal splice acceptor site. All of the mutations except for one were heterozygous. Mutations within the runt domain were found in six of seven patients. Six of seven patients with AML1 mutations were diagnosed with AML, and one had acute lymphoblastic leukemia. In three of these seven patients, AML evolved from other hematologic disorders. AML1 mutations were found in two of four AML-M0 and two of three patients with acquired trisomy 21. Patients with AML1 mutations tended to be older children. Three of four patients with AML1 mutations who received stem cell transplantation (SCT) are alive, whereas the remaining three patients with mutations without SCT died. These results suggest that AML1 mutations in pediatric hematologic malignancies are infrequent, but are possibly related to AML-M0, acquired trisomy 21, and leukemic transformation. These patients may have a poor clinical outcome.
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PMID:AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies. 1287 80

The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in expression of the RUNX1-CBF2T1 [AML1-ETO (AE)] fusion oncogene. AML/ETO may contribute to leukemogenesis by interacting with nuclear corepressor complexes that include histone deacetylases, which mediate the repression of target genes. However, expression of AE is not sufficient to transform primary hematopoietic cells or cause disease in animals, suggesting that additional mutations are required. Activating mutations in receptor tyrosine kinases (RTK) are present in at least 30% of patients with AML. To test the hypothesis that activating RTK mutations cooperate with AE to cause leukemia, we transplanted retrovirally transduced murine bone marrow coexpressing TEL-PDGFRB and AE into lethally irradiated syngeneic mice. These mice (19/19, 100%) developed AML resembling M2-AML that was transplantable in secondary recipients. In contrast, control mice coexpressing with TEL-PDGFRB and a DNA-binding-mutant of AE developed a nontransplantable myeloproliferative disease identical to that induced by TEL-PDGFRB alone. We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate. We found that although imatinib prolonged the survival of treated mice, histone deacetylase inhibitors provided no additional survival benefit. These data demonstrate that an activated RTK can cooperate with AE to cause AML in mice, and that this system can be used to evaluate novel therapeutic strategies.
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PMID:An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. 1288 86

Recent data suggest that late relapses evolve from an ancestral ETV6/RUNX1-positive (also designated TEL/AML1-positive) clone resulting from secondary changes (ETV6 deletion) that differ from those of the initial leukemia and, as a consequence, may also deviate in their clonotypic immunoglobulin/T-cell receptor (IG/TCR) gene rearrangements. The aim of our study was to compare the immunogenotype and fluorescence in situ hybridization (FISH) patterns of the unrearranged ETV6 allele of matched diagnosis/relapse samples from 12 children with an early or late relapse. We identified varying degrees of differences in the IG/TCR in six of them. A clonal change or evolution of the unrearranged ETV6 allele was also observed in six children but remained unchanged in three. However, these two parameters were not in concordance, nor did the immunogenotype pattern correlate with the duration of the first remission. We therefore propose that the potential of the immunogenotype to diversify depends primarily on the stage of IG/TCR gene configuration of the cell in which the ETV6/RUNX1 gene fusion takes place.
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PMID:Clonal variation of the immunogenotype in relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia indicates subclone formation during early stages of leukemia development. 1469 96

We previously isolated different isoforms of a new Ets transcription factor family member, NERF/ELF-2, NERF-2, NERF-1a, and NERF-1b. In contrast to the inhibitory isoforms NERF-1a and NERF-1b, NERF-2 acts as a transactivator of the B cell-specific blk promoter. We now report that NERF-2 and NERF-1 physically interact with AML1 (RUNX1), a frequent target for chromosomal translocations in leukemia. NERF-2 bound to AML1 via an interaction site located in a basic region upstream of the Ets domain. This is in contrast to most other Ets factors such as Ets-1 that bind to AML1 via the Ets domain, suggesting that different Ets factors utilize different domains for interaction with AML1. The interaction between AML1 and NERF-2 led to cooperative transactivation of the blk promoter, whereas the interaction between AML1 and NERF-1a led to repression of AML1-mediated transactivation. To delineate the differences in function of the different NERF isoforms, we determined that the transactivation domain of NERF-2 is encoded by the N-terminal 100 amino acids, which have been replaced in NERF-1a by a 19-amino acid transcriptionally inactive sequence. Furthermore, acidic domains A and B, which are conserved in NERF-2 and the related proteins ELF-1 and MEF/ELF-4, but not in NERF-1a, are largely responsible for NERF-2-mediated transactivation. Because translocation of the Ets factor Tel to AML1 is a frequent event in childhood pre-B leukemia, understanding the interaction of Ets factors with AML1 in the context of a B cell-specific promoter might help to determine the function of Ets factors and AML1 in leukemia.
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PMID:Isoforms of the Ets transcription factor NERF/ELF-2 physically interact with AML1 and mediate opposing effects on AML1-mediated transcription of the B cell-specific blk gene. 1497 Feb 18

Studies of monozygotic twins with concordant leukemia and scrutiny of archived neonatal blood by polymerase chain reaction (PCR) indicated that many pediatric leukemias are initiated prenatally by chromosomal translocation followed by a variable postnatal period before diagnosis of disease. The latter is thought to reflect a persistent preleukemic stage and a requirement for secondary genetic events. We sought to examine this further by examination of blood spots in rare cases of MLL fusion-positive or ETV6/RUNX1 (TEL-AML1) fusion gene-positive acute leukemia that were diagnosed at ages beyond the normal age range. We present evidence that the duration of the postnatal preleukemic state can occasionally be very protracted in these biological subtypes of pediatric leukemia, and we discuss its biological significance.
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PMID:Protracted postnatal natural histories in childhood leukemia. 1497 94

RUNX1 (AML1, CBFA2) is mutated in affected members of families with autosomal dominant thrombocytopenia and platelet dense granule storage pool deficiency. Many of those affected, usually by point mutations in one allele, are predisposed to the development of acute myeloid leukemia (AML) in adult life. The RUNX1 protein complexes with core binding factor beta (CBFB) to form a heterodimeric core binding transcription factor (CBF) that regulates many genes important in hematopoiesis. RUNX1 was first identified as the gene on chromosome 21 that is rearranged by the translocation t(8;21)(q22;q22.12) recurrently found in the leukemic cells of patients with AML. In addition to the t(8;21), RUNX1 is rearranged with one of several partner genes on other chromosomes by somatically acquired translocations associated with hematological malignancies. Point mutations of RUNX1 are also found in sporadic leukemias to reinforce the important position of this gene on the multi-step path to leukemia. In animal models, at least one functional copy of RUNX1 is required to effect definitive embryonic hematopoiesis. Cells expressing dominant-negative mutants of RUNX1 are readily immortalized and transformed, and those RUNX1 mutants which retain CBFB binding ability may possess dominant-negative function. However, in some families there is transmitted one mutated allele of RUNX1 with no dominant-negative function, demonstrating that simple haploinsufficiency of RUNX1 predisposes to AML and also causes a generalized hematopoietic stem cell disorder most recognizable as thrombocytopenia.
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PMID:Familial mutations of the transcription factor RUNX1 (AML1, CBFA2) predispose to acute myeloid leukemia. 1506 Nov 91

In two patients with hematological neoplasias a tandem repetition of chromosome 21 in the bone marrow was revealed by cytogenetic analysis. The disease was different in the two patients: one was of the lymphoid type, acute lymphoblastic leukemia type L1, and the other was of the myeloid type, acute nonlymphoblastic leukemia type M2. In one case this chromosomal abnormality resulted in amplification of the AML1 gene (HUGO nomenclature: RUNX1), whereas in the other case the AML1 gene was not included in the tandem repetition, showing that apparently similar cytogenetic aberrations may be different at the molecular level.
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PMID:Chromosome 21 tandem repetition and AML1 (RUNX1) gene amplification. 1510 77

The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-beta signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.
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PMID:Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. 1513 60

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.
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PMID:Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies. 1513 96


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