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)

As a result of the recurring translocation t(11;16) (q23;p13.3), MLL (mixed-lineage leukemia) is fused in frame to CBP (CREB binding protein). This translocation has been documented almost exclusively in cases of acute leukemia or myelodysplasia secondary to therapy with drugs that target DNA topo isomerase II. The minimal chimeric protein that is produced fuses MLL to the bromodomain, histone acetyltransferase (HAT) domain, EIA-binding domain and steroid-receptor coactivator binding domains of CBP. We show that transplantation of bone marrow retrovirally transduced with MLL-CBP induces myeloid leukemias in mice that are preceded by a long preleukemic phase similar to the myelodysplastic syndrome (MDS) seen in many t(11;16) patients but unusual for other MLL translocations. Structure-function analysis demonstrated that fusion of both the bromodomain and HAT domain of CBP to the amino portion of MLL is required for full in vitro transformation and is sufficient to induce the leukemic phenotype in vivo. This suggests that the leukemic effect of MLL-CBP results from the fusion of the chromatin association and modifying activities of CBP with the DNA binding activities of MLL.
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PMID:Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. 1097 Aug 58

As reported previously, AML1-ETO knock-in mice were generated to investigate the role of AML1-ETO in leukemogenesis and to mimic the progression of t(8;21) leukemia. These knock-in mice died in midgestation because of hemorrhaging in the central nervous system and a block of definitive hematopoiesis during embryogenesis. Therefore, they are not a good model system for the development of acute myeloid leukemia. Therefore, mice were generated in which the expression of AML1-ETO is under the control of a tetracycline-inducible system. Multiple lines of transgenic mice have been produced with the AML1-ETO complementary DNA controlled by a tetracycline-responsive element. In the absence of the antibiotic tetracycline, AML1-ETO is strongly expressed in the bone marrow of AML1-ETO and tet-controlled transcriptional activator double-positive transgenic mice. Furthermore, the addition of tetracycline reduces AML1-ETO expression in double-positive mice to nondetectable levels. Throughout the normal murine lifespan of 24 months, mice expressing AML1-ETO have not developed leukemia. In spite of this, abnormal maturation and proliferation of progenitor cells have been observed from these animals. These results demonstrate that AML1-ETO has a very restricted capacity to transform cells. Either the introduction of additional genetic changes or the expression of AML1-ETO at a particular stage of hematopoietic cell differentiation will be necessary to develop a model for studying the pathogenesis of t(8;21).
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PMID:Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. 1097 55

MLF1 is a novel protein identified as the NPM-MLF1 chimeric protein produced by a t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS), often prior to acute myeloid leukemia (AML), except for M3. The clinical features of t(3;5)-positive myeloid disorders suggest that this chimeric protein is involved in dysregulation of progenitor cells with the capability to differentiate into multiple lineages. So far, involvement of wild-type MLF1 in hematopoiesis or in leukemogenesis has not been fully investigated. In the present study, 65 patients with AML and 44 patients with MDS were tested for the expression of MLF1 using the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. A significantly higher level of MLF1 expression (ratio of MLF1/beta-actin mRNA >0.4) was readily detected in seven of 65 patients with de novo AML, three of 12 with post-MDS AML and seven of 44 with MDS, but not in any patients with ALL (n = 18). According to the FAB classification, high levels of MLF1 were found in patients with relatively immature subtypes of AML (M1, M2, M6 and M7) and high risk MDS (RAEB and RAEB-T). These findings indicate that the pattern of MLF1 expression is identical to the clinical morphology appearing in the t(3;5)-positive myeloid disorders and is correlated to the MDS-associated AML and transformation phase of MDS in t(3;5)-negative myeloid disorders. A CD34+ population of normal bone marrow cells preferentially expressed MLF1 with obviously decreasing levels of expression during maturation. Therefore, MLF1 normally functions in multi-potent progenitor cells and its dysregulation may take part in leukemogenesis from MDS.
Leukemia 2000 Oct
PMID:Elevated MLF1 expression correlates with malignant progression from myelodysplastic syndrome. 1102 51

Formation of the Bcr-Abl chimeric protein is the molecular hallmark of Philadelphia-positive leukemia. Normal Bcr is a complex protein which has been found in the cytoplasm, has serine kinase activity, and has been implicated in cellular signal transduction. However, we have recently demonstrated that Bcr can also associate with condensed chromatin. Since two major Bcr proteins have been characterized (p160Bcr and p130Bcr), we sought to determine if different forms of Bcr localized to the nucleus vs the cytoplasm. Metabolic labeling and Western blotting experiments were performed using nuclear and cytoplasmic extracts of three human Philadelphia-negative leukemia/lymphoma cell lines (KG-1, HL-60, and Jurkat). Both methodologies showed that p160Bcr and p130Bcr localized to the cytoplasm, but the p130 form predominated in the nucleus. These results suggest that Bcr serves both nuclear and cytoplasmic functions, and that different forms of Bcr may be preferentially involved in these distinct activities.
Leukemia 2000 Nov
PMID:Cytoplasmic and nuclear localization of the 130 and 160 kDa Bcr proteins. 1106 24

In most cases of acute promyelocytic leukemia (APL), a fusion of the promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha) genes occurs, resulting in the expression of a PML-RARalpha chimeric protein. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found fusing RARa with other genes. Four variant mutations have been described, and the t(11;17)(q21;q23) translocation generating a promyelocyte leukemia zinc finger (PLZF)-RARalpha fusion gene is the most common. PLZF-RARalpha-positive APL forms a clinically distinct group because unlike PML-RARalpha-positive leukemia, it does not respond to retinoic acid with terminal granulocytic differentiation of the cells, and remissions cannot be achieved with retinoids alone. At the molecular level, this has been explained by the retinoic acid-insensitive binding of corepressor proteins to the PLZF part of the fusion protein, leading to sustained repression of target genes that are important for cellular differentiation. Targeting of the PLZF-RARalpha-bound corepressor complexes using a combination of all-trans retinoic acid (ATRA) and deacetylase inhibitors has shown that the repression of target genes can be relieved, allowing differentiation of the cells. In addition, when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) is applied, the cells may be forced to undergo terminal differentiation, both in vitro and in vivo. This suggests that signals from the activated G-CSF receptor may induce the release of corepressor proteins from PLZF. Together, these findings indicate that PLZF-RARalpha-positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given.
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PMID:Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. 1117 38

The promyelocytic leukemia retinoic acid receptor alpha (PMLRARalpha) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARalpha transgenic mice develop leukemia only after several months, suggesting that PMLRARalpha does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARalpha to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARalpha alone modestly altered neutrophil maturation, the combination of PMLRARalpha and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARalpha and BCL-2 than in mice expressing PMLRARalpha alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARalpha to initiate APL.
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PMID:BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. 1118 7

The MLL (HRX, ALL-1 HTRX) gene at chromosome band 11q23 frequently is rearranged in acute lymphoblastic and myeloblastic leukemia. To date, more than 40 different 11q23 abnormalities have been described on the cytogenetic level, and at least 25 of the respective fusion partner genes are cloned. The vast majority of the respective reciprocal translocations generate a chimeric 5'-MLL/partner-3' gene on the derivative 11q23. In this work, we report a unique ins(X;11)(q24;q23) in an infant with acute myeloid leukemia (AML-M2) that fuses the human KIAA0128 gene at Xq24 with MLL. In contrast to the typical reciprocal MLL translocations, however, we provide evidence that the 5'-MLL/KIAA0128-3' fusion resides on Xq24 rather than on 11q23. The KIAA0128 gene encodes the human Septin 6 protein, which contains an ATP-GTP binding motif and three nuclear targeting sequences in its carboxy terminus. The maintenance of the reading frame of the 5'-MLL/KIAA0128-3' mRNA fusion allows for the formation of a novel chimeric protein. Septin 6 is the third member of the Septins that is fused to the MLL protein; the other two are hCDCrel at 22q11 and MSF at 17q25.
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PMID:An ins(X;11)(q24;q23) fuses the MLL and the Septin 6/KIAA0128 gene in an infant with AML-M2. 1147 64

The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expression of AML1-ETO is under the control of the human MRP8 promoter (hMRP8-AML1-ETO). AML1-ETO is specifically expressed in myeloid cells, including common myeloid progenitors of hMRP8-AML1-ETO transgenic mice. The transgenic mice were healthy during their life spans, suggesting that AML1-ETO alone is not sufficient for leukemogenesis. However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia. Our results provide direct evidence that AML1-ETO is critical for causing myeloid leukemia, but one or more additional mutations are required for leukemogenesis. The hMRP8-AML1-ETO-transgenic mice provide an excellent model that can be used to isolate additional genetic events and to further understand the molecular pathogenesis of AML1-ETO-related leukemia.
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PMID:AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. 1152 43

T(8;21) AML1(CBFA2)-ETO(MTG8) is the most common chromosomal translocation in acute myeloid leukemia (AML) in both children and adults. We sought to understand the structure and gain insight into the fusion process between AML1 and ETO by sequencing genomic fusions in 17 primary childhood AMLs and two cell lines with t(8;21). Reciprocal translocations were sequenced for seven of the 19 samples. We assumed a null hypothesis that the translocation breakpoints would be evenly distributed along the intronic breakpoint cluster regions. Testing for multimodality via smoothed bootstrap statistical methods suggested, however, the presence of two separate cluster regions within both the AML1 and ETO breakpoint cluster regions. ETObreakpoints were predominantly located in intron 1B in a defined cluster 5' of exon 1A (scan statistic P value = 0.00001). All patients with available RNA expressed an AML1-ETO mRNA fusion between exon 5 of AML1 and exon 2 of ETO. Since the structural restraints for the fusion protein of AML1-ETO exclude exon 1A, we reason that ETO intron 1B harbors a structural feature with propensity for breakage and/or recombination. Chromosomal breakpoints displayed evidence of fusion by a non-homologous end joining process, with microhomologies and nontemplate nucleotides at some fusion junctions. Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed.
Leukemia 2001 Dec
PMID:Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. 1175 12

Acquired chromosomal anomalies (most commonly translocations) in lymphoma and leukemia usually result in either activation of a quiescent gene (by means of immunoglobulin or T-cell-receptor promotors) and expression of an intact protein product, or creation of a fusion gene encoding a chimeric protein. This review summarizes current immunocytochemical studies of these 2 categories of oncogenic protein, with emphasis on the clinical relevance of their detection in diagnostic samples. Among the quiescent genes activated by rearrangement, expression of cyclin D1 (due to rearrangement of the CCND1 [BCL-1] gene) is a near-specific marker of t(11;14) in mantle cell lymphoma; BCL-2 expression distinguishes follicular lymphoma cells from their nonneoplastic counterparts in reactive germinal centers and appears to be an independent prognostic marker in diffuse large cell lymphoma; and TAL-1 (SCL) expression identifies T-cell acute lymphoblastic neoplasms in which this gene is activated. The protein products of other genes activated by chromosomal rearrangement have a role as markers of either lineage (eg, PAX-5 [B-cell-specific activator protein] for B cells, including B-lymphoblastic neoplasms), or maturation stage (eg, BCL-6 for germinal-center and activated B cells and MUM-1/IRF4 for plasma cells). Currently, no hybrid protein encoded by fusion genes is reliably detectable by antibodies recognizing unique junctional epitopes (ie, epitopes absent from the wild-type constituent proteins). Nevertheless, staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RARalpha is highly distinctive. Similarly, antibodies to the anaplastic lymphoma kinase (ALK) tyrosine kinase are valuable (because wild-type ALK is not found in normal lymphoid tissue) in detecting neoplasms (CD30-positive large T-cell lymphomas) with t(2;5) or its variants. Thus, immunocytochemical detection of the products of many rearranged genes in lymphoma and leukemia can be clinically informative and provide information on cellular and subcellular protein expression that cannot be inferred from studies based on messenger RNA.
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PMID:Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. 1178 Dec 20


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