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)

Proteins encoded by Polycomb and Trithorax-group (Pc-G and Trx-G) genes regulate developmental fates by maintaining or repressing HOX gene expression, respectively. In a search for candidate myeloid leukemia tumor suppressor genes from a approximately 2.5 Mb commonly-deleted segment within chromosome band 7q22, we identified a novel human Trithorax (Trx) family member named MLL5. Trx-G genes encode proteins that modulate transcriptional programs through protein-protein interactions that are mediated by PHD and SET domains, and by binding to DNA via A-T hooks and methyltransferase homology motifs. MLL5 is a homolog of the Drosophila gene CG9007; it encodes a 6.5 kb mRNA that is expressed widely. MLL5 includes a SET domain and a single PHD finger, but lacks A-T hooks and methyltransferase homology domains that are found in MLL. The leukemia cell line RCV-ACV-A carries a heterozygous missense mutation within the PHD domain; however, no mutations within the MLL5 coding region were detected in primary leukemias. MLL5 is a novel mammalian Trx-G gene that might modulate transcription by protein association.
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PMID:MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. 1210 24

The mixed-lineage leukemia gene (MLL, ALL1, HRX) encodes a 3,969-amino-acid nuclear protein homologous to Drosophila trithorax and is required to maintain proper Hox gene expression. Chromosome translocations in human leukemia disrupt MLL (11q23), generating chimeric proteins between the N terminus of MLL and multiple translocation partners. Here we report that MLL is normally cleaved at two conserved sites (D/GADD and D/GVDD) and that mutation of these sites abolishes the proteolysis. MLL cleavage generates N-terminal p320 (N320) and C-terminal p180 (C180) fragments, which form a stable complex that localizes to a subnuclear compartment. The FYRN domain of N320 directly interacts with the FYRC and SET domains of C180. Disrupting the interaction between N320 and C180 leads to a marked decrease in the level of N320 and a redistribution of C180 to a diffuse nuclear pattern. These data suggest a model in which a dynamic post-cleavage association confers stability to N320 and correct nuclear sublocalization of the complex, to control the availability of N320 for target genes. This predicts that MLL fusion proteins of leukemia which would lose the ability to complex with C180 have their stability conferred instead by the fusion partners, thus providing one mechanism for altered target gene expression.
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PMID:Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization. 1248 72

Human SET encodes a nuclear phosphoprotein with a highly acidic carboxyl-terminus, forming a SET-CAN fusion gene in a patient with acute undifferentiated leukemia. SET is highly conserved between species and is ubiquitously expressed, suggesting a widespread biological role. Even though SET is involved in chromatin remodeling and transcriptional activation, its precise role in hematopoietic cells and the contribution of SET-CAN to leukemogenesis remains unknown. We determined the effect of tetracycline-regulatable expression of SET, a deletion mutant of SET, and SET-CAN on the human promonocytic cell line U937T. The expression of SET and SET-CAN inhibited proliferation of these cells. SET accomplishes this through the induction of the differentiation program, an effect that depends on the presence of its acidic domain. SET-CAN most likely inhibits growth by interfering with hCRM1, but it also partially blocks differentiation. Our results are the first demonstration of a potential role of SET in hematopoietic differentiation.
Leukemia 2004 Feb
PMID:Effects of SET and SET-CAN on the differentiation of the human promonocytic cell line U937. 1467 43

Galpha(12), the alpha-subunit of the G12 family of heterotrimeric G proteins is involved in the regulation of cell proliferation and neoplastic transformation. GTPase-deficient, constitutively activated mutant of Galpha(12) (Galpha(12)Q229L or Galpha(12)QL) has been previously shown to induce oncogenic transformation of NIH3T3 cells promoting serum- and anchorage-independent growth. Reduced growth-factor dependent, autonomous cell growth forms a critical defining point at which a normal cell turns into an oncogenic one. To identify the underlying mechanism involved in such growth-factor/serum independent growth of Galpha(12)QL-transformed NIH3T3, we carried out a two-dimensional differential proteome analysis of Galpha(12)QL-transformed NIH3T3 cells and cells expressing vector control. This analysis revealed a total of 22 protein-spots whose expression was altered by more than 3-folds. Two of these spots were identified by MALDI-MS analysis as proliferating cell nuclear antigen (PCNA) and myeloid-leukemia-associated SET protein. The increased expressions of these proteins in Galpha(12)QL cells were validated by immunoblot analysis. Furthermore, transient transfection studies with NIH3T3 cells indicated that the expression of activated Galpha(12) readily increased the expression of SET protein by 24 h. As SET has been previously reported to be an inhibitor of phosphatase PP2A, the nuclear phosphatase activity was monitored in cells expressing activated Galpha(12). Our results indicate that the nuclear phosphatase activity is inhibited by greater than 50% in Galpha(12)QL cells compared to vector control cells. Thus, our results from differential proteome analysis presented here report for the first time a role for SET in Galpha(12)-mediated signaling pathways and a role for Galpha(12) in the regulation of the leukemia-associated SET-protein expression.
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PMID:Proteome analysis of NIH3T3 cells transformed by activated Galpha12: regulation of leukemia-associated protein SET. 1559 26

Rearrangements of the mixed-lineage leukemia gene MLL1 (MLL, HRX, ALL1), the human homologue of the Drosophila gene trithorax, are associated with aggressive acute leukemias in both children and adults. Transformation by rearranged forms of MLL1, including in-frame fusion proteins, partial tandem duplications, and amplification of MLL1 through upregulation of Hox gene and cofactor expression apparently results in a block in hematopoietic differentiation. MLL1 regulates Hox gene expression via direct promoter binding and histone H3 Lys 4 methylation mediated by the intrinsic methyltransferase activity of the SET domain. Mll1 knockout leads to loss of Hox gene expression, defects in hematopoiesis, and embryonic lethality. A close homologue, MLL2 is amplified in some solid tumors. MLL2 also has histone H3 Lys 4 methyltransferase activity that is dependent on menin, a protein mutated in multiple neoplasia type I (MEN1) and which is required for normal Hox expression. These findings underscore the importance of the MLL histone methyltransferases in development and disease.
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PMID:Mechanisms of transformation by MLL. 1566 55

The mixed-lineage leukemia (MLL) gene is a trithorax group (trxG) gene that was originally identified at chromosomal translocations in patients developing acute leukemia. Although Polycomb group (PcG) genes, which counteract trxG genes, were found to play essential roles in hematopoiesis, little has been understood about the roles of trxG genes in hematopoiesis except for MLL. MLL has been found fused with 1 of more than 30 different partner genes to yield a diverse collection of MLL fusion oncoproteins that lead to the aberrant expression of HOX genes. Recent studies have revealed that MLL assembles, as do some trxG proteins, into a chromatin-modifying transcriptional regulatory supercomplex to regulate epigenetic pathways, including the methylation of histone H3 lysine 4, which is conferred by the Su (var)3-9, enhancer of zeste, and tritho-rax (SET) domain. Other studies also indicated that MLL plays a nonredundant and essential role in definitive hematopoiesis and induces the proliferation and differentiation of hematopoietic progenitors by maintaining appropriate up-regulation of HOX genes. Further progress in the field will provide novel insights into trxG- and PcG-mediated hematopoiesis and help us understand the epigenetic process by which developing stem cells coordinate proliferation and differentiation.
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PMID:Roles of a trithorax group gene, MLL, in hematopoiesis. 1591 56

Human SET, a target of chromosomal translocation in human leukemia encodes a highly conserved, ubiquitously expressed, nuclear phosphoprotein. SET mediates many functions including chromatin remodeling, transcription, apoptosis and cell cycle control. We report that overexpression of SET directs differentiation of the human promonocytic cell line U937 along the dendritic cell (DC) pathway, as cells display typical morphologic changes associated with DC fate and express the DC surface markers CD11b and CD86. Differentiation occurs via a calcium-dependent mechanism involving the CaMKII and MAPK/ERK pathways. Similar responses are elicited by interferon-gamma (IFN-gamma) treatment with the distinction that IFN-gamma signaling activates the DNA-binding activity of STAT1 whereas SET overexpression does not. In addition, unlike IFN-gamma signaling, SET generated stress-induced p38/MAPK activity. Interestingly, IFN-gamma treatment transiently upregulated endogenous SET in a dose-dependent manner. These results suggest that SET is part of both IFN-gamma-mediated and stress-mediated cellular responses and that SET induces cell differentiation via calcium and MAPK/ERK pathways.
Leukemia 2005 Aug
PMID:SET-induced calcium signaling and MAPK/ERK pathway activation mediate dendritic cell-like differentiation of U937 cells. 1593 Dec 63

Chromosome translocations involving the mixed lineage leukemia gene MLL are associated with aggressive acute leukemias in both children and adults. Leukemogenic MLL fusion proteins delete the MLL SET domain Lys(4) methyltransferase activity and fuse MLL to 1 of >40 different translocation partners. Some MLL fusion proteins involve nuclear proteins that are transcriptional activators, whereas others have transcriptional activating activity but instead dimerize the truncated MLL molecule. Both types of MLL fusion proteins enforce persistent expression of Hox a9 and Meis1, which is pivotal for leukemogenesis through mechanisms that remain obscure. Here, we show that nuclear and dimerizable forms of MLL bind with a similar pattern to the Hox a9 locus that overlaps the distribution of wild-type MLL and deregulate transcription of three isoforms of Hox a9. Induction of MLL fusion protein activity is associated with increased levels of histone acetylation and Lys(4) methylation at Hox target genes. In addition, the MLL-ENL-ER protein, but not dimerized MLL, also induces dimethylation of histone H3 at Lys(79), suggesting alternative mechanisms for transcriptional activation.
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PMID:Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. 1635 44

A mutation in the JH2 pseudokinase domain of the Janus kinase 2 gene (JAK2 V617F) has been described in chronic myeloproliferative disorders (MPD). We screened 79 acute myeloid leukemia (AML) cell lines and found five positive for JAK2 V617F (HEL, MB-02, MUTZ-8, SET-2, UKE-1), 4/5 with histories of MPD/MDS. While SET-2 expressed both mutant (mu) and wild-type (wt) JAK2, remaining positives carried homo-/hemizygous JAK2 mutations. Microsatellite analysis confirmed losses of heterozygosity (LOH) affecting the JAK2 region on chromosome 9p in MB-02, MUTZ-8 and UKE-1, but also in HEL, the only JAK2mu cell line lacking any reported MPD/MDS history. All five JAK2mu cell lines displayed cytogenetic hallmarks of MDS, namely losses of 5q or 7q, remarkably in 4/5 cases affecting both chromosomes. Our combined FISH and microsatellite analysis uncovered a novel mechanism to supplement mitotic recombination previously proposed to explain JAK2 LOH, namely chromosome deletion with/without selective JAK2mu amplification. Confirming the importance of the mutated JAK2 protein for growth and prevention of apoptosis, JAK2mu cell lines displayed higher sensitivities to JAK2 inhibition than JAK2wt cell lines. In summary, JAK2 V617F cell lines, derived from patients with history of MPD/MDS, represent novel research tools for elucidating the pathobiology of this JAK2 mutation.
Leukemia 2006 Mar
PMID:JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders. 1640 98

Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy.
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PMID:The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. 1641 55


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