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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 655-663
NEOPLASIA
From the Cancer Genomics Division, National Cancer
Center Research Institute, Tokyo, Japan.
The AML1-MTG8 fusion transcription factor generated by t(8;21)
translocation is thought to dysregulate genes that are crucial for
normal differentiation and proliferation of hematopoietic progenitors
to cause acute myelogenous leukemia (AML). Although AML1-MTG8 has been
shown to repress the transcription of AML1 targets, none of the known
targets of AML1 are probably responsible for AML1-MTG8-mediated
leukemogenesis. In this study, 24 genes under the downstream control of
AML1-MTG8 were isolated by using a differential display technique.
Analysis with deletion mutants of AML1-MTG8 demonstrated that the
regulation of the majority of these genes requires the region of 51 residues (488-538) containing the Nervy homology region 2 (NHR2),
through which AML1-MTG8 interacts with MTGR1. Among the 24 genes
identified, 10 were considered to be genes under the control of AML1,
because their expression was altered by AML1b or AML1a or both.
However, the other 14 genes were not affected by either AML1b or AML1a,
suggesting the possibility that AML1-MTG8 regulates a number of
specific target genes that are not normally regulated by AML1.
Furthermore, an up-regulated gene, TIS11b (ERF-1,
cMG1), was highly expressed in t(8;21) leukemic cells, and the
overexpression of TIS11b induced myeloid cell proliferation in
response to granulocyte colony-stimulating factor. These results suggest that the high-level expression of TIS11b contributes to AML1-MTG8-mediated leukemogenesis.
(Blood. 2000;96:655-663)
Transcription factor genes are the frequent targets of
chromosomal translocations associated with human leukemia.
Translocation leads to the dysregulation of downstream target genes
under the control of the transcription factor and ultimately results in differentiation arrest and aberrant proliferation of hematopoietic progenitor cells.1 The t(8;21)(q22;q22) translocation is
observed in approximately 40% of acute myeloid leukemia subtype M2
(AML-M2)2 and juxtaposes the AML1 gene3
on chromosome 21, which encodes a transcription factor, with the
MTG8 (ETO) gene on chromosome 8, generating the
AML1-MTG8 (ETO) fusion transcription factor.4-7 This fusion
protein consists of the N-terminal portion of AML1 fused in frame to
the nearly full-length MTG8.
AML1 forms heterodimeric complexes with CBF The AML1-MTG8 fusion protein contains the DNA-binding domain (RHD) of
AML1 and the MTG8 portion that interacts with the N-CoR/mSin3/HDAC corepressor complex,38-40 but lacks the C-terminal region
of AML1 that interacts with the p300 and CBP histone acetyltransferase coactivators.16 Therefore, AML1-MTG8 could recruit HDAC
activity instead of histone acetylase to the promoter of
AML1-responsive target genes, resulting in histone deacetylation and
transcriptional repression. Reporter assays have shown that AML1-MTG8
dominantly inhibits AML1-dependent transactivation of the TCR We previously found that ectopic expression of AML1-MTG8 in L-G cells
induces G-CSF-dependent cell proliferation and blocks differentiation
to mature neutrophils.34 These findings opened the
possibility that L-G cells might be suitable for differential screening
and that some of the genes whose expression is altered in
AML1-MTG8-expressing cells might affect myeloid cell proliferation and
differentiation. In this study, we identified 24 downstream genes of
AML1-MTG8 by a differential display technique. We show here that the
region containing NHR2, through which AML1-MTG8 interacts with
MTGR1,34 plays a major role in AML1-MTG8-mediated regulation in L-G cells, and that AML1-MTG8 may not only repress the
transcription of AML1 target genes but also regulate specific downstream genes. In addition, we demonstrate that the TIS11b (ERF-1, cMG1) gene46-48 may contribute
to AML1-MTG8-mediated leukemogenesis.
Cells and retroviruses
Patient samples
Plasmid construction The pLNSX-derived plasmids for HA-tagged AML1-MTG8, AML1b, AML1a, AML1-MTG8 538, and AML1-MTG8487 were described
previously.34 A pLNCX-derived plasmid for the expression of
HA-tagged AML1a was constructed by inserting AML1a complementary
DNA(cDNA) digested with StuI and ClaI and treated with
Klenow polymerase into a HpaI site of pLNCX. The cDNA for
HA-tagged mouse TIS11b was produced by performing RT-PCR on the total
RNA of L-G cells. The PCR primers were designed to introduce
an HA-tag at the N-terminus and HindIII sites at both
ends, and had the following sequences:
5'-AAGCTTAGGCCTCTAGACCATGGCATACCCATACGACGTGCCT- GACTACGCCTCCACCACCACCCTCGTGTCCGC-3'
and 5'-AAGCTTAGTCATCTGAGATGGAGAG-3'. This TIS11b cDNA was
digested with HindIII, and cloned into a HindIII site
of pLNCX. The integrity of the insert was confirmed by nucleotide sequencing.
Differential display analysis Total RNAs were isolated by the acid guanidinium thiocyanate/phenol/chloroform method52 from the retrovirus-infected L-G cells that had been cultivated in the presence of IL-3 and harvested within the 5-day period after G418 selection. Differential display analysis was performed essentially as described by Ito et al.53 Briefly, cDNAs were synthesized by using 4 oligo-dT primers (GT15MN; M = A+C+G, n = A, C, G, or T) and SuperScript II reverse transcriptase (Gibco-BRL, Rockville, MD). PCR amplification was carried out between the same oligo-dT primers and arbitrary 10-mers (Operon Technologies, Alameda, CA) using Taq DNA polymerase (Perkin-Elmer, Norwalk, CT or Boehringer Mannheim, Mannheim, Germany). A thermal cycling profile composed of 1 cycle of 94°C for 3 minutes, 40°C for 5 minutes, and 72°C for 5 minutes, and 24 cycles of 95°C for 15 seconds, 40°C for 2 minutes, and 72°C for 1 minute followed by an extension step at 72°C for 5 minutes was used. The reaction products were separated by 6% native polyacrylamide gel electrophoresis and detected by FluorImager SI (Amersham Pharmacia Biotech, Uppsala, Sweden) after staining of the gel with SYBR Green I (Amresco, Solon, OH). Bands that displayed more than 3-fold visible differences in intensity were excised from the gel and reamplified by PCR using the same set of primers. The reamplified products were cloned into a plasmid vector, pGEM-T Easy (Promega, Madison, WI), and sequenced. The cloned cDNA fragments were confirmed to correspond to the bands that we identified, by Southern blotting of the differential display reaction products using the cDNA fragments as probes. The identities of the sequences and their homologies to already known sequences were determined by performing BLAST searches in the Genbank/EMBL/DDBJ database. The nucleotide sequences of cDNA fragments were registered with the DDBJ database. Their data appear in the Genbank/EMBL/DDBJ database with the accession numbers AB030390 to AB030433.Northern blotting Total RNAs were isolated by the acid guanidinium thiocyanate/phenol/chloroform method. Five micrograms of each RNA was electrophoresed on a 1.0% agarose gel containing 2.2 mol/L formaldehyde in 20 mmol/L MOPS pH 7.0/8 mmol/L sodium acetate/1 mmol/L EDTA, and transferred to Hybond-N membranes (Amersham Pharmacia Biotech). To examine the tissue specificity of gene expression, a human multiple tissue Northern (MTN) blot (Clontech, Palo Alto, CA) was used. Hybridization was performed at 42°C for 20 hours in 6 × standard saline citrate (SSC)/10% dextran sulfate/1% sodium dodecyl sulfate (SDS)/1 × Denhardt's solution/50% formamide/100 µg/mL denatured salmon sperm DNA. The membranes were washed several times in 0.1 × SSC/0.1% SDS at 65°C, and the hybridized transcripts were detected with a BAS2000 image analyzer (Fuji Film, Tokyo, Japan). The cloned cDNA fragments in pGEM-T Easy were used as hybridization probes after EcoRI digestion and agarose gel electrophoresis purification. The probe for the human TIS11b gene was produced by RT-PCR on total RNA from the bone marrow cells of a t(8;21) AML patient. The PCR primers were designed according to the known cDNA sequence as follows: 5'-CCACCTAACATAAGGACAAGT-3' and 5'-CTTCCTGCAGACCTACACAA-3'. To confirm the amount of RNA loaded onto each lane, all membranes were successively hybridized with human glyceraldehide-3-phosphate-dehydrogenase (G3PDH) or -actin
cDNA probe (Clontech).
Western blotting Cells were harvested and suspended in 62.5 mmol/L Tris-HCl pH 6.8/2% SDS/5%-mercaptoethanol/10% glycerol at
2 × 107 cells/mL. After boiling and centrifugation,
cell lysates were electrophoresed with 10% SDS-polyacrylamide gels and
transferred to Hybond ECL membranes (Amersham Pharmacia Biotech) by
electroblotting. The membranes were blocked in 5% low-fat milk
dissolved in PBS containing 0.1% Tween-20 (PBS-T) at room temperature
for 2 hours or at 4°C overnight, and incubated at room temperature
for 1 hour with the anti-HA monoclonal antibody (3F10, Boehringer
Mannheim) dissolved in PBS-T. After washing with PBS-T, the membranes
were incubated at room temperature for 1 hour with horseradish
peroxidase-conjugated second antibody dissolved in PBS-T. After
extensive washing with PBS-T, the immunocomplexes were visualized by an
ECL detection system (Amersham Pharmacia Biotech).
Identification of genes whose expression is altered by AML1-MTG8 The L-G cell is an IL-3-dependent murine myeloid precursor cell line that can be induced to differentiate into mature neutrophils in response to G-CSF.49 Ectopic expression of AML1-MTG8 in L-G cells induces G-CSF-dependent cell proliferation and blocks differentiation into mature neutrophils.34 To identify genes involved in AML1-MTG8-mediated leukemogenesis, we applied the differential display technique53,54 using RNA from control L-G cells and L-G cells ectopically expressing AML1-MTG8. From 1600 differential display reactions obtained by using 400 arbitrary 10-mers and 4 oligo-dT primers in different combinations, we obtained 49 cDNA bands that displayed more than 3-fold visible differences in intensity. The reproducibility of the differential expression pattern was confirmed by using more than 3 pairs of L-G infectants infected with control and AML1-MTG8-carrying retroviruses at different times. Each band was excised from the gel, reamplified, and cloned, resulting in the isolation of 47 differentially expressed cDNA clones except for 2 bands that resisted reamplification. Sequencing analysis and database searching of these 47 clones led to the identification of 24 nonredundant genes (Table 1). These 24 genes consisted of 19 genes up-regulated by AML1-MTG8, which we termed AMUGs, and 5 genes down-regulated by AML1-MTG8, which we termed AMDGs. Eight of the 19 AMUGs and 1 of the 5 AMDGs did not have any significant homology with known genes in the database. None of these genes has been previously identified as being regulated by AML1-MTG8 or AML1, except for the granzyme B gene previously described as a putative target of AML1.25
The regulation of the majority of AMUGs and AMDGs requires the region containing NHR2 To examine the importance of the NHR2 portion of AML1-MTG8 in the alteration in expression of AMUGs and AMDGs, we investigated their differential expression patterns in L-G cells expressing C-terminal deletion mutants of AML1-MTG8 (538 and 487) using the
differential display technique and Northern blotting (Figure 1B and C). The region of 51 residues
(488-538) containing NHR2 is essential for complex formation between
AML1-MTG8 and MTGR1 as well as for induction of G-CSF-dependent
proliferation and differentiation arrest of L-G cells.34
The 538 mutant lacks NHR3 and NHR4 but retains NHR2, whereas the
487 mutant is devoid of NHR2 as well as NHR3 and NHR4 (Figure 1A).
As summarized in Table 1, most of the genes were differentially
expressed by 538 like the wild-type AML1-MTG8, whereas no genes were
differentially expressed by 487. This result indicates that the
regulation of the majority of these genes requires the region
containing NHR2. Exceptionally, the expression of Grb10 and
Stefin 3 was not affected by 538, indicating that the regulation
of these genes requires the region containing NHR3 and NHR4. In
addition, it was puzzling that the expression of MRP14 was
repressed by 538 despite being induced by AML1-MTG8.
Regulation of AMUGs and AMDGs by AML1b and AML1a AML1-MTG8 blocks AML1-dependent transcriptional activation. To examine whether AML1b alters the expression of AMUGs and AMDGs, we investigated their differential expression patterns in L-G cells overexpressing AML1b using the differential display technique and Northern blotting (Figure 2). Surprisingly, AML1b altered the expression of only 6 of the 24 genes as summarized in Table 1. The exogenously expressed AML1b protein, however, may not alter the expression of some AML1b-regulated genes, because L-G cells express AML1b endogenously. Thus, we investigated the differential expression patterns of AMUGs and AMDGs in L-G cells overexpressing AML1a (Figure 2), which was thought to function as a competitive inhibitor of AML1b. AML1a lacks the transactivation domain and has been shown to interfere with AML1b-activated transcription of the TCR
enhancer.43 Besides, overexpression of AML1a inhibits myeloid cell differentiation and stimulates cell proliferation of
32Dcl3 in response to G-CSF, and this effect is canceled by the
concomitant overexpression of AML1b.55 We previously
reported that overexpression of AML1a in L-G cells by the SV40 promoter of LNSX vector does not stimulate cell proliferation in response to
G-CSF.34 However, we show here that further overexpression of AML1a by the cytomegalovirus promoter of the LNCX
vector can induce cell proliferation in response to G-CSF (Figure
3), although it does not inhibit
differentiation as fully as AML1-MTG8 (data not shown). The cells that
overexpressed AML1a showed slight growth retardation in the presence of
IL-3-like cells overexpressing AML1-MTG8 (data not shown). In this
system, AML1a is considered to competitively inhibit the function of
AML1b. Thus the CMV promoter-directed overexpression of AML1a is
expected to alter the expression of the masked AML1b-regulated genes.
The expression of all the genes affected by the exogenously expressed
AML1b protein, such as MRP14, A6C520, stefin 3,
B16G120, granzyme B, and uridine phosphorylase, was altered by the overexpression of AML1a with the same
pattern as seen with AML1-MTG8. In addition, among 18 genes unaffected by the exogenously expressed AML1b protein, the overexpression of AML1a
altered the expression of 4 genes with the same pattern as seen with
AML1-MTG8. This result indicates that these 4 genes are under the
downstream control of AML1b and have been fully regulated by endogenous
AML1b. The other 14 genes may be regulated in an AML1b-independent
manner.
Overexpression of the TIS11b gene induced myeloid cell proliferation in response to G-CSF and delayed granulocytic differentiation To examine whether the genes identified in this study actually have an effect on cell proliferation or differentiation, we introduced AMUGs and AMDGs into L-G cells and AML1-MTG8-expressing L-G cells, respectively, and then examined G-CSF-dependent growth and differentiation. We evaluated the effect of Grb10, Pim-2, and TIS11b overexpression as candidates. Although overexpression of Grb10 and Pim-2 did not affect cell proliferation and differentiation (data not shown), overexpression of TIS11b clearly induced G-CSF-dependent cell proliferation as shown in Figure 4A, with the growth rate decreasing after days 10 to 12. We confirmed the exogenous expression of TIS11b in L-G cells by Northern blotting analysis (Figure 4B) and by Western blotting analysis with the anti-HA antibody (Figure 4C). The TIS11b expression was maintained up to day 14 (data not shown). To examine whether TIS11b inhibits granulocytic differentiation, we chronologically followed the cell morphology of the L-G infectants in the presence of G-CSF. Before G-CSF treatment, we could not find any significant difference in cell morphology between AML1-MTG8- and TIS11b-expressing cells and control cells (data not shown). After 7 days of cultivation in the presence of G-CSF, the majority of the control cells differentiated into mature granulocytes containing segmented nuclei, whereas AML1-MTG8-expressing cells maintained an immature morphology even after day 12 as shown in Figure 4D. On the other hand, TIS11b-expressing cells had not fully differentiated at day 7, and the majority of the cells comprised promyelocyte-, myelocyte-, and metamyelocyte-like immature cells. At day 12, the cell population consisted of myeloid elements in all stages of maturation, containing 20% to 30% mature granulocytes. Thus, TIS11b delayed the maturation of the L-G cells but did not block their terminal differentiation as completely as AML1-MTG8.
Expression of the TIS11b gene is increased in leukemic cells carrying t(8;21) To examine whether TIS11b gene expression is associated with leukemia phenotypes, we compared the TIS11b gene expression in leukemia cell lines carrying t(8;21) (Kasumi-1 and SKNO1) to the expression in myeloid cell lines without t(8;21) (ML1, KG1, NB4, and HL60), a monocyte cell line (U937), erythroid cell lines (HEL, K562), and lymphoid cell lines (Namalwa and MOLT-4) by Northern blotting. As shown in Figure 5A, Kasumi-1 and SKNO1 cells displayed significantly higher expression of TIS11b compared to the monocyte and other myeloid cell lines. Erythroid and lymphoid leukemia cell lines also showed high expression of TIS11b. As well, TIS11b gene expression was higher in bone marrow cells from patients with t(8;21) AML-M2 compared to non-t(8;21) AML-M2 cells and the controls. These findings are compatible with the results showing that TIS11b gene expression is elevated in L-G cells expressing AML1-MTG8.
In this report, we identified 24 genes whose expression was altered by AML1-MTG8 in myeloid precursor cells. Nineteen were up-regulated by AML1-MTG8 (AMUGs) and 5 were down-regulated by AML1-MTG8 (AMDGs). None of these genes has ever been identified as being regulated by AML1-MTG8, although the granzyme B gene was expected to be regulated by AML1 on the basis of promoter analysis.25 In addition to granzyme B, the TIS11b, Pim-2 and mast cell carboxypeptidase A genes have putative AML1-binding sites within their promoters. On the other hand, the MRP14, monocyte/neutrophil elastase inhibitor, and uridine phosphorylase genes have no AML1-binding sites within their known promoter sequences. At present, however, it is unknown whether the genes identified in this study are regulated directly or indirectly. Some of them may be secondary targets whose expression is regulated by transcription factors that are induced or repressed by AML1-MTG8 or regulated in a more complex manner. However, even though these genes are regulated indirectly, our results provide important information on AML1-MTG8-mediated transcriptional regulation and leukemogenesis.
We thank Dr A. D. Miller for providing retrovirus vectors, Dr D. Baltimore for providing BOSC23 cells, Dr T. Honjyo for providing L-G cells, and Dr T. Ito for suggestions about the mRNA differential display technique. We also thank M. Mori and C. Hatanaka for technical assistance. We are grateful to Drs M. Sasaki, K. Sugita, S. Tanitsu, T. Ishii, and H. Takeuchi for providing patient samples.
Submitted November 11, 1999; accepted March 2, 2000.
Supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science and Culture; by a grant from the Special Coordination Funds for the Promotion of Science and Technology from the Science and Technology Agency; by a Grant-in-Aid for the 2nd Term Comprehensive 10-year Strategy for Cancer Control and a Research Grant on Human Genome and Gene Therapy from the Ministry of Health and Welfare; and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Drug ADR Relief, R&D Promotion, and Product Review of Japan. H. S. and S. N. are Awardees of Research Resident Fellowships from the Foundation for Promotion of Cancer Research in Japan.
Reprints: Hitoshi Ichikawa, Cancer Genomics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: hichikaw{at}ncc.go.jp.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
1. Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994;372:143-149[Medline] [Order article via Infotrieve]. 2. Mitelman F, Heim S. Quantitative acute leukemia cytogenetics. Genes Chromosomes Cancer. 1992;5:57-66[Medline] [Order article via Infotrieve].
3.
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M.
t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.
Proc Natl Acad Sci U S A.
1991;88:10431-10434
4.
Erickson P, Gao J, Chang KS, et al.
Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.
Blood.
1992;80:1825-1831
5.
Kozu T, Miyoshi H, Shimizu K, et al.
Junctions of the AML1/MTG8 (ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction.
Blood.
1993;82:1270-1276 6. Miyoshi H, Kozu T, Shimizu K, et al. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J. 1993;12:2715-2721[Medline] [Order article via Infotrieve]. 7. Nisson PE, Watkins PC, Sacchi N. Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. Cancer Genet Cytogenet. 1992;63:81-88[Medline] [Order article via Infotrieve]. 8. Ogawa E, Inuzuka M, Maruyama M, et al. Molecular cloning and characterization of PEBP2, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2. Virology. 1993;194:314-331[Medline] [Order article via Infotrieve].
9.
Ogawa E, Maruyama M, Kagoshima H, et al.
PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene.
Proc Natl Acad Sci U S A.
1993;90:6859-6863
10.
Wang S, Wang Q, Crute BE, Melnikova IN, Keller SR, Speck NA.
Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor.
Mol Cell Biol.
1993;13:3324-3339 11. Daga A, Tighe JE, Calabi F. Leukaemia/Drosophila homology. Nature. 1992;356:484[Medline] [Order article via Infotrieve]. 12. Kagoshima H, Shigesada K, Satake M, et al. The runt domain identifies a new family of heteromeric transcriptional regulators. Trends Genet. 1993;9:338-341[Medline] [Order article via Infotrieve].
13.
Meyers S, Downing JR, Hiebert SW.
Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: The runt homology domain is required for DNA binding and protein-protein interactions.
Mol Cell Biol.
1993;13:6336-6345
14.
Kania MA, Bonner AS, Duffy JB, Gergen JP.
The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system.
Genes Dev.
1990;4:1701-1713
15.
Miyoshi H, Ohira M, Shimizu K, et al.
Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia.
Nucleic Acids Res.
1995;23:2762-2769 16. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J. 1998;17:2994-3004[Medline] [Order article via Infotrieve]. 17. Ogryzko VV, Schiltz RL, Rusanova V, Howard BH, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953-959[Medline] [Order article via Infotrieve]. 18. Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani YA. p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature. 1996;382:319-324[Medline] [Order article via Infotrieve]. 19. Kwok RPS, Lundblad JR, Chrivia JC, et al. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature. 1994;370:223-226[Medline] [Order article via Infotrieve].
20.
Shoemaker SG, Hromas R, Kaushansky K.
Transcriptional regulation of interleukin 3 gene expression in T lymphocytes.
Proc Natl Acad Sci U S A.
1990;87:9650-9654 21. Frank R, Zhang J, Meyers S, Hiebert SW, Nimer SD. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene. 1995;11:2667-2674[Medline] [Order article via Infotrieve].
22.
Takahashi A, Satake M, Yamaguchi-Iwai Y, et al.
Positive and negative regulation of granulocyte-macrophage colony stimulating factor promoter activity by AML1-related transcription factor, PEBP2.
Blood.
1995;86:607-616
23.
Zhang DE, Fujioka K, Hetherington CJ, et al.
Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1).
Mol Cell Biol.
1994;14:8085-8095
24.
Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD.
PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells.
Mol Cell Biol.
1994;14:5558-5568
25.
Babichuk CK, Bleackley RC.
Mutational analysis of the murine granzyme B gene promoter in primary T cells and a T cell clone.
J Biol Chem.
1997;272:18564-18571
26.
Prosser HM, Wotton D, Gegonne A, et al.
A phorbol ester response element within the human T-cell receptor -chain enhancer.
Proc Natl Acad Sci U S A.
1992;89:9934-9938
27.
Redondo JM, Pfohl JL, Hernandez-Munain C, Wang S, Speck NA, Krangel MS.
Indistinguishable nuclear factor binding to functional core sites of the T-cell receptor and murine leukemia virus enhancers.
Mol Cell Biol.
1992;12:4817-4823
28.
Niki M, Okada H, Takano H, et al.
Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor.
Proc Natl Acad Sci U S A.
1997;94:5697-5702 29. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell. 1996;84:321-330[Medline] [Order article via Infotrieve].
30.
Sasaki K, Yagi H, Bronson RT, et al.
Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor .
Proc Natl Acad Sci U S A.
1996;93:12359-12363
31.
Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA.
Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.
Proc Natl Acad Sci U S A.
1996;93:3444-3449 32. Wang Q, Stacy T, Miller JD, et al. The CBFB subunit is essential for CBFA2 (AML1) function in vivo. Cell. 1996;87:697-708[Medline] [Order article via Infotrieve].
33.
Erickson PF, Robinson M, Owens G, Drabkin HA.
The ETO portion of acute myeloid leukemia t(8;21) fusion transcript encodes a highly evolutionary conserved, putative transcription factor.
Cancer Res.
1994;54:1782-1786
34.
Kitabayashi I, Ida K, Morohoshi F, et al.
The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8 (ETO/CDR) family, MTGR1.
Mol Cell Biol.
1998;18:846-858
35.
Gamou T, Kitamura E, Hosoda F, et al.
The partner gene of AML1 in t(16;21) myeloid malignancies in a novel member of the MTG8 (ETO) family.
Blood.
1998;91:4028-4037 36. Feinstein PG, Kornfeld K, Hogness DS, Mann RS. Identification of homeotic target genes in Drosophila melanogaster including nervy, a proto-oncogene homologue. Genetics. 1995;140:573-586[Abstract].
37.
Erickson PF, Dessev G, Lasher RS, Philips G, Robinson M, Drabkin HA.
ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: implications for t(8;21) leukemogenesis and monitoring residual disease.
Blood.
1996;88:1813-1823
38.
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA.
Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO.
Mol Cell Biol.
1998;18:7185-7191
39.
Lutterbach B, Westendorf JJ, Linggi B, et al.
ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors.
Mol Cell Biol.
1998;18:7176-7184
40.
Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM.
ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex.
Proc Natl Acad Sci U S A.
1998;95:10860-10865 41. Alland L, Muhle R, Hou H, et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997;387:49-55[Medline] [Order article via Infotrieve]. 42. Heinzel T, Lavinsky RM, Mullen TM, et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997;387:43-48[Medline] [Order article via Infotrieve]. 43. Meyers S, Lenny N, Hiebert SW. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995;15:1974-1982[Abstract]. 44. Yergeau DA, Hetherington CJ, Wang Q, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet. 1997;15:303-306[Medline] [Order article via Infotrieve].
45.
Okuda T, Cai Z, Yang S, et al.
Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors.
Blood.
1998;91:3134-3143 46. Barnard RC, Pascall JC, Brown KD, McKay IA, Williams NS, Bustin SA. Coding sequence of ERF-1, the human homologue of Tis11b/cMG1, members of the Tis11 family of early response genes. Nucleic Acids Res. 1993;20:3580. 47. Gomperts M, Pascall JC, Brown KD. The nucleotide sequence of a cDNA encoding an EGF-inducible gene indicates the existence of a new family of mitogen-induced genes. Oncogene. 1990;5:1081-1083[Medline] [Order article via Infotrieve].
48.
Varnum BC, Ma Q, Chi T, Fletcher B, Herschman HR.
The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat.
Mol Cell Biol.
1991;11:1754-1758
49.
Kinashi T, Kwang HL, Ogawa M, et al.
Premature expression of the macrophage-colony stimulating factor receptor on a multipotential stem cell line does not alter differentiation lineages controlled by stromal cells used for coculture.
J Exp Med.
1991;173:1267-1279
50.
Pear WS, Nolan GP, Scott ML, Baltimore D.
Production of high-titer helper-free retroviruses by transient transfection.
Proc Natl Acad Sci U S A.
1993;90:8392-8396 51. Miller AD, Miller DG, Garcia JV, Lynch CM. Use of retroviral vectors for gene transfer and expression. Methods Enzymol. 1993;217:581-599[Medline] [Order article via Infotrieve]. 52. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156-159[Medline] [Order article via Infotrieve]. 53. Ito T, Kito K, Adati N, Mitusi Y, Hagiwara H, Sakaki Y. Fluorescent differential display: arbitrary primed RT-PCR fingerprinting on an automated DNA sequencer. FEBS Lett. 1994;351:231-236[Medline] [Order article via Infotrieve].
54.
Liang P, Pardee AB.
Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction.
Science.
1992;257:967-971 55. Tanaka T, Tanaka K, Ogawa S, et al. An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. EMBO J. 1995;14:341-350[Medline] [Order article via Infotrieve]. 56. Lenny N, Meyers S, Hiebert SW. Functional domains of the t(8;21) fusion protein, AML-1/ETO. Oncogene. 1995;11:1761-1769[Medline] [Order article via Infotrieve].
57.
Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW.
The t(8;21) fusion product, AML1/ETO, associates with C/EBP
58.
Rhoades KL, Hetherington CJ, Rowley JD, et al.
Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis.
Proc Natl Acad Sci U S A.
1996;93:11895-11900
59.
Klampfer L, Zhang J, Zelenetz AO, Uchida H, Nimer SD.
The AML1/ETO fusion protein activates transcription of BCL-2.
Proc Natl Acad Sci U S A.
1996;93:14059-14064
60.
Lutterbach B, Sun D, Schuetz J, Hiebert SW.
The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein.
Mol Cell Biol.
1998;18:3604-3611 61. Ooi J, Yajnik V, Immanuel D, et al. The cloning of Grb10 reveals a new family of SH2 domain proteins. Oncogene. 1995;10:1621-1630[Medline] [Order article via Infotrieve]. 62. Bai RY, Jahn T, Schrem S, et al. The SH2-containing adapter protein GRB10 interacts with BCR-ABL. Oncogene. 1998;17:941-948[Medline] [Order article via Infotrieve]. 63. van der Lugt NM, Domen J, Verhoeven E, et al. Proviral tagging in E mu-myc transgenic mice lacking the Pim-1 proto-oncogene leads to compensatory activation of Pim-2. EMBO J. 1995;14:2536-2544[Medline] [Order article via Infotrieve]. 64. Mochizuki T, Kitanaka C, Noguchi K, et al. Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation. Oncogene. 1997;15:1471-1480[Medline] [Order article via Infotrieve]. 65. Herschman HR. Primary response genes induced by growth factors and tumour promoters. Annu Rev Biochem. 1991;60:281-319[Medline] [Order article via Infotrieve].
66.
DuBois RN, McLane MW, Ryder K, Lau LF, Nathans D.
A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence.
J Biol Chem.
1990;265:19185-19191
67.
Lai WS, Stumpo DJ, Blackshear PJ.
Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein.
J Biol Chem.
1990;265:16556-16563 68. Varnum BC, Lim RW, Sukhatme VP, Herschman HR. Nucleotide sequence of a cDNA encoding TIS11, a message induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate. Oncogene. 1989;4:119-120[Medline] [Order article via Infotrieve].
69.
Carballo E, Lai WS, Blackshear PJ.
Feedback inhibition of macrophage tumor necrosis factor-
70.
Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ.
Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA.
Mol Cell Biol.
1999;19:4311-4323
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  S. Park, W. Chen, T. Cierpicki, M. Tonelli, X. Cai, N. A. Speck, and J. H. Bushweller Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity Blood, April 9, 2009; 113(15): 3558 - 3567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Jawa, S. Anillo, and M. N. Kulaylat Transfusion-Related Acute Lung Injury J Intensive Care Med, March 1, 2008; 23(2): 109 - 121. [Abstract] [PDF]
|
|
|
|
 |
|
 J.-R. J. Yeh, K. M. Munson, Y. L. Chao, Q. P. Peterson, C. A. MacRae, and R. T. Peterson AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression Development, January 15, 2008; 135(2): 401 - 410. [Abstract] [Full Text] [PDF]
|
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L. F. Peterson, M. Yan, and D.-E. Zhang The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO Blood, May 15, 2007; 109(10): 4392 - 4398. [Abstract] [Full Text] [PDF]
|
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|
|
|
L.-H. Ma, H. Liu, H. Xiong, B. Chen, X.-W. Zhang, Y.-Y. Wang, H.-Y. Le, Q.-H. Huang, Q.-H. Zhang, B.-L. Li, et al. Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis Blood, January 15, 2007; 109(2): 769 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Choi, K. E. Elagib, L. L. Delehanty, and A. N. Goldfarb Erythroid Inhibition by the Leukemic Fusion AML1-ETO Is Associated with Impaired Acetylation of the Major Erythroid Transcription Factor GATA-1. Cancer Res., March 15, 2006; 66(6): 2990 - 2996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Mulloy, V. Jankovic, M. Wunderlich, R. Delwel, J. Cammenga, O. Krejci, H. Zhao, P. J. M. Valk, B. Lowenberg, and S. D. Nimer AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion PNAS, March 15, 2005; 102(11): 4016 - 4021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Silliman, D. R. Ambruso, and L. K. Boshkov Transfusion-related acute lung injury Blood, March 15, 2005; 105(6): 2266 - 2273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Wang, G.-B. Zhou, T. Yin, B. Chen, J.-Y. Shi, W.-X. Liang, X.-L. Jin, J.-H. You, G. Yang, Z.-X. Shen, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec PNAS, January 25, 2005; 102(4): 1104 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Hug, N. Ahmed, J. A. Robbins, and M. A. Lazar A Chromatin Immunoprecipitation Screen Reveals Protein Kinase C{beta} as a Direct RUNX1 Target Gene J. Biol. Chem., January 9, 2004; 279(2): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal, B. Sargin, B. Steffen, I. Matsumura, Y. Kanakura, F. D. Bohmer, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations Blood, April 15, 2003; 101(8): 3164 - 3173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Kalev-Zylinska, J. A. Horsfield, M. V. C. Flores, J. H. Postlethwait, M. R. Vitas, A. M. Baas, P. S. Crosier, and K. E. Crosier Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1-CBF2T1 transgene advances a model for studies of leukemogenesis Development, March 6, 2003; 129(8): 2015 - 2030. [Abstract] [Full Text] [PDF]
|
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|
|
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B. A. Hug, S. Y. D. Lee, E. L. Kinsler, J. Zhang, and M. A. Lazar Cooperative Function of Aml1-ETO Corepressor Recruitment Domains in the Expansion of Primary Bone Marrow Cells Cancer Res., May 1, 2002; 62(10): 2906 - 2912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Mulloy, J. Cammenga, K. L. MacKenzie, F. J. Berguido, M. A. S. Moore, and S. D. Nimer The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood, January 1, 2002; 99(1): 15 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Nahm, S. K. Woo, J. S. Handler, and H. M. Kwon Involvement of multiple kinase pathways in stimulation of gene transcription by hypertonicity Am J Physiol Cell Physiol, January 1, 2002; 282(1): C49 - C58. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2,6-syalyltransferase,
and interferon-induced mRNA was specifically altered by AML1-MTG8 but
not altered by either AML1b or AML1a.
