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

The t(8;21) translocation is one of the most frequent translocations in acute myeloid leukaemia (AML), giving rise to the AML1-ETO fusion protein (or RUNX1-CBF2T1). This abnormality is associated with myelocytic leukaemia with dysplastic granulopoiesis. Here, we demonstrate that when expressed in a normal human (CD34(+)) progenitor population, AML1-ETO selectively inhibits granulocyte colony formation but not monocyte colony formation. In bulk liquid culture, we found that though AML1-ETO transiently inhibited the proliferation of CD34(+) cells, it promoted long-term growth of myeloid cells for more than 80 days, suggesting that differentiation was inhibited. In support of this, cultures expressing AML1-ETO demonstrated enhanced retention of colony-forming capacity. Phenotypic examination of AML1-ETO cultures revealed a defect in granulocytic differentiation in terms of retention of CD34(+) cells within the culture and delayed CD11b upregulation. Morphologically, granulocyte terminal differentiation in AML1-ETO-expressing cells was inhibited by 83+/-5%, giving rise to a build-up of early to intermediate granulocytes that exhibited a number of morphological features associated with t(8;21) leukaemias. In contrast, AML1-ETO had little or no effect on monocytic differentiation. Taken together, these results suggest that expression of AML1-ETO selectively inhibits the differentiation of granulocytic cells and promoted extensive self-renewal, supporting a causal role for t(8;21) translocations in leukaemogenesis.
Leukemia 2004 Jul
PMID:Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal. 1515 69

The t(12;21) translocation, which generates the TEL-AML1 (ETV6-RUNX1) fusion gene, is the most common structural chromosome change in childhood cancer and is exclusively associated with the common B cell precursor subset of acute lymphoblastic leukemia (ALL). Evidence suggests that the translocation usually occurs in utero during fetal hemopoiesis and most probably constitutes an initiating or first-hit mutation that is necessary but insufficient for the development of overt, clinical leukemia. The mechanism by which TEL-AML1 contributes to this early stage of leukemogenesis is unknown. To address this question we have analyzed hemopoiesis in mice syngeneically transplanted with TEL-AML1-transduced bone marrow stem cells. TEL-AML1 expression was associated with an accumulation/expansion of primitive c-kit-positive multipotent progenitors and a modest increase in myeloid colony-forming cells. TEL-AML1 expression was, however, permissive for myeloid differentiation. Analysis of B lymphopoiesis revealed an increase in early, pro-B cells but a differentiation deficit beyond that stage, resulting in reduced B cell production in the marrow. TEL-AML1-positive B cell progenitors exhibited reduced expression of the surrogate light-chain component lambda5 and the IL-7 receptor, both of which may contribute to impedance of differentiation in vivo and account for their reduced in vitro clonogenicity in IL-7. A selective differentiation deficit of B lineage progenitors (i) is consistent with the phenotype of TEL-AML1-associated leukemia in children and (ii) provides a potential mechanism for the protracted preleukemic state that often precedes ALL. These results provide mechanistic insight into the role of the t(12;21) translocation in the initiation of common B cell precursor ALL.
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PMID:Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. 1515 99

Runt-related (RUNX) gene family is composed of three members, RUNX1/AML1, RUNX2 and RUNX3, and encodes the DNA-binding (alpha) subunits of the Runt domain transcription factor polyomavirus enhancer-binding protein 2 (PEBP2)/core-binding factor (CBF), which is a heterodimeric transcription factor. RUNX1 is most frequently involved in human acute leukemia. RUNX2 shows oncogenic potential in mouse experimental system. RUNX3 is a strong candidate as a gastric cancer tumor suppressor. The beta subunit gene of PEBP2/CBF is also frequently involved in chromosome rearrangements associated with human leukemia. In this Overview, I will summarize how this growing field has been formed and what are the challenging new frontiers for better understanding of the oncogenic potential of this gene family.
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PMID:Oncogenic potential of the RUNX gene family: 'overview'. 1515 73

RUNX family members are DNA-binding transcription factors that regulate the expression of genes involved in cellular differentiation and cell cycle progression. The RUNX family includes three mammalian RUNX proteins (RUNX1, -2, -3) and two homologues in Drosophila. Experiments in Drosophila and mouse indicate that the RUNX proteins are required for gene silencing of engrailed and CD4, respectively. RUNX-mediated repression involves recruitment of corepressors such as mSin3A and Groucho as well as histone deacetylases. Furthermore, RUNX1 and RUNX3 associate with SUV39H1, a histone methyltransferase involved in gene silencing. RUNX1 is frequently targeted in human leukemia by chromosomal translocations that fuse the DNA-binding domain of RUNX1 to other transcription factors and corepressor molecules. The resulting leukemogenic fusion proteins are transcriptional repressors that form stable complexes with corepressors, histone deacetylases and histone methyltransferases. Thus, transcriptional repression and gene silencing through RUNX1 contribute to the mechanisms of leukemogenesis of the fusion proteins. Therapies directed at the associated cofactors may be beneficial for treatment of these leukemias.
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PMID:Role of RUNX family members in transcriptional repression and gene silencing. 1515 76

Insights into the pathogenesis of human leukemia have relied heavily on studies of the identified chromosomal translocations found in this group of malignant diseases. Acquired, balanced translocations in acute myelogenous leukemia (AML) generally involve transcriptional regulatory genes, whereas in the myeloproliferative disorders tyrosine kinases are frequently involved. These rearrangements alter the function of at least one and often both of the involved genes. In this review, we focus on the AML1-ETO (a.k.a. RUNX1-ETO) fusion protein, which is found in t(8;21)+ AML. Expression of AML1-ETO in human hematopoietic stem cells (HSCs) preferentially enhances their maintenance, as opposed to their differentiation. The direct effects of AML1-ETO on human and murine HSCs, and the potentially cooperating events that may contribute to its leukemogenic properties, are discussed.
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PMID:Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. 1515 80

A common chromosomal translocation in acute myeloid leukemia (AML) involves the AML1 (acute myeloid leukemia 1, also called RUNX1, core binding factor protein (CBF alpha), and PEBP2 alpha B) gene on chromosome 21 and the ETO (eight-twenty one, also called MTG8) gene on chromosome 8. This translocation generates an AML1-ETO fusion protein. t(8;21) is associated with 12% of de novo AML cases and up to 40% in the AML subtype M2 of the French-American-British classification. Furthermore, it is also reported in a small portion of M0, M1, and M4 AML samples. Despite numerous studies on the function of AML1-ETO, the precise mechanism by which the fusion protein is involved in leukemia development is still not fully understood. In this review, we will discuss structural aspects of the fusion protein and the accumulated knowledge from in vitro analyses on AML1-ETO functions, and outline putative mechanisms of its leukemogenic potential.
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PMID:The 8;21 translocation in leukemogenesis. 1515 81

Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5' region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression.
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PMID:Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. 1515 84

The RUNX1/AML1 gene is the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as another mode of genetic alteration in development of leukemia. Monoallelic germline mutations in RUNX1 result in familial platelet disorder predisposed to acute myelogenous leukemia (FPD/AML). Sporadic point mutations are frequently found in three leukemia entities: AML M0 subtype, MDS-AML, and secondary (therapy-related) MDS/AML. Therapy-related leukemias resulting from anticancer treatments are not uncommon, and the incidence of RUNX1 point mutations appears comparable to the incidence of the t(8;21) AML M2 subtype and the inv(16) AML M4Eo subtype. Half of the point mutations in M0 cases are biallelic, although the frequency varies with ethnicity. Most of the RUNX1 mutations are clustered in the Runt domain and result in defective DNA binding but active beta-subunit binding, which is consistent with three-dimensional structural findings and may explain the dominant inhibitory effects. Unlike the classical tumor suppressor genes requiring biallelic inactivation, haploinsufficient RUNX1 is apparently leukemogenic. However, RUNX1 abnormalities per se are insufficient to cause full-blown leukemia. Intensive investigation of cooperating genetic alterations should elucidate leukemic mechanisms.
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PMID:Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. 1515 85

Inv(16)(p13q22) is associated with acute myeloid leukemia subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This chromosomal rearrangement results in the fusion of CBFB and MYH11 genes. CBF beta normally interacts with RUNX1 to form a transcriptionally active nuclear complex. The MYH11 gene encodes the smooth muscle myosin heavy chain. The CBF beta-SMMHC fusion protein is capable of binding to RUNX1 and form dimers and multimers through its myosin tail. Previous results from transgenic mouse models show that Cbfb-MYH11 is able to inhibit dominantly Runx1 function in hematopoiesis, and is a key player in the pathogenesis of leukemia. In recent years, molecular and cellular biological studies have led to the proposal of several models to explain the function of CBF beta-SMMHC. In this review, we will first focus our attention on the molecular mechanisms proposed in the recent publications. We will next examine recent gene expression profiling studies on inv(16) leukemia cells. Finally, we will describe a recent study from one of our labs on the identification of cooperating genes for leukemogenesis with CBFB-MYH11.
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PMID:Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. 1515 86

Human chromosomal translocation t(12;21)(p12;q22) is one of the most frequent rearrangement in human leukemia, and produces the TEL/RUNX1 fusion protein. The TEL/RUNX1 fusion protein creates a transcriptional repressor that interferes in dominant fashion with RUNX1-dependent transactivation. Here, we demonstrate that the repressor activity of TEL/ RUNX1 differs from that of TEL, even though both TEL and TEL/RUNX1 interact with the nuclear hormone co-repressor (N-CoR) and histone deacetylase (mSin3A) in vivo. Co-immunoprecipitation experiments demonstrated that TEL/RUNX1 forms homodimers in vivo, and heterodimerizes with the TEL when the two proteins are expressed together. These interactions require the HLH (helix-loop-helix) region of TEL. Immunoprecipitation and immunofluorescence analysis showed that p300 interacts with TEL/RUNX1 and is sequestered in the cytoplasm by it. These results suggest that the p300-TEL/RUNX1 complex and heterodimerization of TEL/RUNX1 with TEL may be responsible for the ability of TEL/RUNX1 to inhibit RUNX1-mediated transactivation. It appears that loss of TEL function activates a pathway that cooperates with TEL/RUNX1 and sequesters coactivator(s) into nonfunctional complex in the cytoplasm thus inhibiting transcription of target genes.
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PMID:Mechanism of transcriptional repression by TEL/RUNX1 fusion protein. 1517 33


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