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Molecular Biology and Genetics |
Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine [B. A. H., S. Y. D. L., E. L. K., J. Z., M. A. L.] and Pathology [B. A. H., E. L. K.], and The Penn Diabetes Center [M. A. L.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In cellular assays, AML1-ETO produces two distinct phenotypes (14 , 15) . Consistent with its role as an oncogene, AML1-ETO inhibits differentiation of hematopoietic cell lines (13 , 16, 17, 18, 19, 20, 21) and promotes long-term expansion of primary bone marrow cells in vitro (22, 23, 24, 25) . Nevertheless, AML1-ETO does not appear to cause leukemia in vivo in the absence of cooperating mutations (25 , 26) . Paradoxically, AML1-ETO also inhibits proliferation by slowing G1 to S phase progression when expressed in U937, NIH3T3, 32D, and CD34+ cells (14 , 15 , 25 , 27, 28, 29) . These opposing activities may, in part, be responsible for the difficulty in producing an animal model of leukemia associated with AML1-ETO (22, 23, 24, 25, 26 , 30) . Cells expressing the oncoprotein may be required to escape proliferation arrest to demonstrate the differentiation block and produce leukemia in vivo (14) , or AML1-ETO may have different effects on committed versus primitive hematopoietic stem cells (25) .
AML1-ETO exerts its activities by opposing AML1. In transient expression assays, AML1-ETO represses promoters with putative AML1-binding sites (18 , 31, 32, 33) . In vivo, hemizygous expression of AML1-ETO recapitulates the AML1 loss-of-function phenotype (6 , 7 , 22 , 30) . AML1-ETO interacts with the corepressors SMRT, N-CoR, mSin3, HDAC1, and HDAC2 and likely achieves its antagonism of AML1 through interactions with repression complexes (11, 12, 13) . Furthermore, immunoprecipitation experiments using ETO and the homologous protein ETO-2 suggest that AML1-ETO also has the potential to interact with HDACs 3, 6, and 8 (34) . Pull-down experiments using in vitro-translated components have shown that direct contacts are made with N-CoR and SMRT through the NH4 domain and with Sin3 through the NH2 domain and flanking sequences (12 , 13 , 16 , 35) . The NH2 domain also allows multimerization with ETO-family members and potentially promotes indirect interactions with corepressor molecules (16 , 21 , 31 , 36) . Regions outside of the NH domains may also be able to interact with corepressor proteins, but the relative activities of these regions in cooperation with the other domains remain to be defined (11 , 34) . The corepressor complex or complexes recruited by AML1-ETO in bone marrow progenitors likely depend strongly on the NH2 and NH4 domains.
Recently, numerous corepressor complexes have been biochemically purified from HeLa cell extracts, and the stoichiometric components have been analyzed by mass spectroscopy. The Sin3 complex includes HDAC1, HDAC2, and numerous other proteins but does not include N-CoR or SMRT (37) . The SMRT core complex includes HDAC3 and a novel protein TBL1 but does not include Sin3 (38 , 39) . Several N-CoR complexes have been purified from HeLa cells. One resembles the SMRT/TBL1/HDAC3 complex (39) . Another includes chromatin remodeling components from the SWI/SNF family, as well as the repressor KAP-1 (40) . A third includes Sin3, Sap30, HDAC1, HDAC2, and HDAC3 (40) . The diversity of complexes raises the question of whether AML1-ETO interacts with multiple corepressor complexes through its NH domains or whether transforming activity is derived from interaction with a single complex.
Numerous groups have attempted to gain insight into this question by studying mutations of AML1-ETO’s NH2 and NH4 domains in functional assays (Table 1)
. The results, however, have been conflicting. In some cell lines, NH2 and NH4 contribute unique repression activities, and deletion of either region completely eliminates the activity of AML1-ETO. In other cell types, the domains have redundant activities with minimal deletion phenotypes. Cell type-specific differences in corepressor complexes likely explain the variation in the behavior of similar NH domain mutations. To mimic the corepressor environment of the myeloid progenitor, we modeled the oncogenic activities of AML1-ETO using progenitor-enriched primary bone marrow cells. In assays of differentiation, proliferation, and long-term expansion, individual deletions of NH2 and NH4 show small effects on AML1-ETO function, and deletion of NH2 plus NH4 yields a phenotype more severe than the sum of the individual mutations.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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NH2 mutation removes residues 483–540. The NH4 mutation truncates the protein at residue 663. Ecotropic retrovirus was produced using the BOSC23 packaging cell line as described previously (41)
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Cell Culture.
Bone marrow was harvested from femurs and tibias of BALB/c mice. Lin-cells were purified by immunomagnetic negative selection using the Stem sep progenitor enrichment system (Stem Cell Technologies) to deplete cultures of cells positive for CD5, B220, Mac-1, Gr-1, and Ter119. Depletion was confirmed by FACS analysis using the same antibody cocktail and avidin-conjugated PerCP. Cells were cultured and transduced as described previously (41)
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FACS Analysis.
Cells were washed with PBS and stained for FACS analysis by standard methods (41)
. Briefly, antimouse CD16/CD32 (PharMingen) was used to block Fc receptors. Cells were stained with anti-Gr-1-PE and anti-Mac-1 biotin/PerCP avidin (PharMingen). Isotype control antibodies were used to confirm specificities of signals. Forward scatter versus FL1 (GFP) dot plots were used to gate transduced cells. Cell cycle analysis was performed using the BrdUrd flow kit (PharMingen) with a phychoerythrin-conjugated anti-BrdUrd antibody according to the manufacturer’s instructions. Flow cytometry analysis was performed on a FACSCalibur (Becton Dickinson).
Differentiation Assay.
Lin-bone marrow transduced with retroviral constructs was cultured in medium described above except G-CSF (20 ng/ml; Peprotech) replaced the listed cytokines. After 7 days, cells were washed with PBS and stained for FACS analysis as described above.
Proliferation Assays.
Lin-bone marrow cells (105) were plated in a volume of 1 ml. Cells were counted and split weekly. The fraction of GFP-positive cells was determined by FACS analysis and used to determine the absolute number of transduced cells in culture. Counts were normalized to exactly 104 GFP-positive cells on day 1. BrdUrd incorporation was measured at the times indicated. Cells were cultured in BrdUrd (30 mM) for 1 h. Staining and analysis were performed as described above.
Western Blot.
Lysates were prepared from cells using radioimmunoprecipitation assay buffer. Western blots were hybridized with anti-Flag primary antibody (Sigma). Bands were visualized using Supersignal Femto (Pierce) according to the manufacturer’s instructions.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Refs. 11
, 13
, 16
, 17
, 21
, 27
, 33
, and 42, 43, 44, 45, 46, 47
) suggest that deletions of NH2 and NH4 have different effects on the function of AML1-ETO in different hematopoietic and nonhematopoietic cell types. Assays of NH2 and NH4 function have included those affecting transcription, differentiation, and proliferation. Unfortunately, no consistent pattern of activity has emerged. Both NH2 and NH4 have been shown to individually account for 0 to 
100% of the activity of the fusion protein, depending on the cell line examined. Variability has been observed even when the same laboratory has used the same constructs in different cells (Table 1)
.
AML1-ETO Inhibits Differentiation, Inhibits Proliferation, and Promotes Long-term Expansion of Progenitor-enriched Bone Marrow Cells.
Given the cell-specific functions of the repression domains of AML1-ETO, we examined the activity of the fusion protein using cells that would mimic the corepressor environment of myeloid blasts. Progenitor-enriched primary bone marrow cells were collected by immunomagnetic negative selection and transduced with the MigR1 retroviral vector (encoding GFP; Ref. 41
) or with AML1-ETO MigR1. A single bicistronic message encodes both AML1-ETO and GFP so cells expressing the oncoprotein can be identified readily using FACS analysis.
AML1-ETO interferes with the differentiation of numerous cell lines (13
, 16, 17, 18, 19, 20, 21)
. To investigate the inhibition of differentiation using the described retroviral transduction system, cells were cultured in G-CSF, and the myeloid differentiation markers Gr-1 and Mac-1 were measured on GFP-positive cells after 7 days. A portion (68%) of GFP-positive cells in control cultures expressed Gr-1 and Mac-1 (Fig. 1A)
. In contrast, only 20% of GFP-positive cells from AML1-ETO cultures expressed Gr-1 and Mac-1. Differentiation of untransduced cells was similar to the GFP-transduced control cultures (data not shown). These results confirm that AML1-ETO is able to inhibit the differentiation of primary bone marrow cells.
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. This is consistent with recent data showing that AML1-ETO inhibits short-term proliferation of human CD34+ cells (25)
. Incorporation of BrdUrd by untransduced cells was similar to the MigR1 control (data not shown). Thus, AML1-ETO is capable of exerting blocks in both differentiation and proliferation in acutely transduced primary bone marrow cells.
We next transduced Lin-cells with MigR1 or AML1-ETO MigR1 constructs and monitored cultures by counting cells and performing weekly FACS analysis for 1 month (Fig. 1C)
. Although the fraction of GFP-positive cells in the control culture remained constant, the fraction of cells expressing AML1-ETO first plummeted and later rebounded (Fig. 1C
, left). Cell counts indicated that cells transduced with AML1-ETO persisted in culture (Fig. 1C
, right), and these cells continued to incorporate BrdUrd at day 28 (Fig. 1D)
. Untransduced cells from both cultures behaved like cells expressing GFP alone (data not shown). By 6–8 weeks, AML1-ETO cultures were comprised of >90% GFP-positive cells (data not shown). The cells from long-term cultures were morphologically blast like (Fig. 1E)
, positive for low levels of c-kit, and negative for Gr-1, Mac-1, B220, CD5, and Sca-1 (data not shown), consistent with an immature nature. AML1-ETO expression was detectable by Western blot analysis (data not shown). This ability of AML1-ETO to promote long-term expansion of primary bone marrow cells was consistent with what others have reported (22, 23, 24, 25)
.
Previous studies have shown that AML1-ETO can cause apoptosis in U937 cells (14) . However, in our system, primary bone marrow cells expressing AML1-ETO did not bind more annexin than controls, suggesting that apoptosis was not significantly compromising the expansion of cultures (data not shown). We also did not detect apoptosis when similar experiments were performed in U937 cells (data not shown). This apparent conflict with previous studies is likely the result of differences in the level of expression of AML1-ETO and is a subject of ongoing investigation.
Structure Function Analysis of AML1-ETO NH Domains.
The preceding studies established three phenotypic consequences of AML1-ETO expression in primary bone marrow cells: (a) inhibition of differentiation; (b) inhibition of proliferation; and (c) increased self-renewal. This system was then used to examine the roles of the NH2 and NH4 domains of AML1-ETO that have been implicated in corepressor recruitment. We designed a series of deletion mutations and expressed them from the MigR1 retroviral vector described above (Fig. 2A)
. We deleted the AML1-ETO residues 483–540 that include the NH2 domain and sequences immediately flanking it. This region interacts directly with endogenous ETO-family members, as well as Sin3 (16
, 21
, 34, 35, 36)
. Additionally, we truncated AML1-ETO at residue 663 to remove the NH4 domain. This region interacts with SMRT and its homologue, N-CoR (11, 12, 13
,35)
. Finally, we constructed a double mutation of NH2 and NH4. Previous functional assays of AML1-ETO have always shown the elimination of activity by deletions of both NH2 and NH4 (Table 1)
. Although we are unable to determine protein levels in acutely transduced bone marrow cells because of the few cells used in these assays, mean GFP fluorescence values suggest that the retroviral constructs express mutant proteins at levels comparable with that of AML1-ETO (data not shown). Additionally, Western blot analysis of transfected 293 cells shows that each construct produces a protein of predicted size (Fig. 2B)
. The series of NH mutants should be able to reveal whether NH2 and NH4 independently are redundant or essential to the activity of AML1-ETO.
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. The results of multiple differentiation assays are summarized in Fig. 2D
. The deletion of NH2 on average increased the number of Gr-1+/Mac-1+ cells from 15 to 28%, representing a 35% reduction in the activity of AML1-ETO. The deletion of NH4 had no effect. By contrast to the single deletions, the double deletion of NH2 and NH4 eliminated the activity of the fusion protein. Thus, the NH2 and NH4 domains function cooperatively to inhibit differentiation.
NH2 and NH4 Cooperatively Interfere with Primary Bone Marrow Cell Proliferation.
We were interested in determining whether the proliferation of primary bone marrow cells was responsive to the NH domain mutations. We measured the synthesis of new DNA by pulsing cells with BrdUrd for 1 h and measuring incorporation (Fig. 3A)
. A portion (41%) of the cells transduced with MigR1 incorporated BrdUrd compared with 15% of cells transduced with AML1-ETO. The deletion of NH2 and NH4 separately did not significantly increase incorporation of BrdUrd, although an upward trend was noted in the case of NH2, suggesting a subtle effect. Again, the double mutation completely eliminated the activity of AML1-ETO (Fig. 3B)
. Proliferation assays supported the BrdUrd studies (Fig. 3C)
. These data indicate that in primary bone marrow cells, the double deletion of NH2 and NH4 relieves inhibition of proliferation far more than the sum of the individual deletions.
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. BrdUrd incorporation by cells of 6-week-old cultures was comparable with that of wild-type AML1-ETO (data not shown). In contrast, cells transduced with GFP alone or with the double mutant could not be maintained. Although we cannot rule out that different subpopulations of cells expand in response to different AML1-ETO mutants, the cells were similar in morphology and surface marker phenotype to those cells transduced with AML1-ETO (data not shown). These results suggest that NH2 and NH4 do not individually provide essential activities that promote the expansion of primary bone marrow cells by AML1-ETO.
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. The mean fluorescence of the NH2 and NH4 mutant cells were 7.4- and 3-fold, respectively, higher than wild type. The results of Western blot analysis also revealed increased average expression of the mutant proteins in the long-term cultures (data not shown). Thus, although the mutants qualitatively retain the ability to promote self-renewal, the requirement for increased expression of the mutants suggests a quantitative reduction in function.
We also tested the effects of expressing the DNA-binding domain of AML1 by itself. This protein lacks the repression domain of ETO but is also missing the transactivation domain of wild-type AML1. We reasoned that if AML1-ETO functions by active repression of AML1 target genes, the AML1 DNA-binding domain alone might be able to promote long-term expansion of cells via passive competition with endogenous AML1. Indeed, cells transduced with AML1 1–177(1–177) survive in long-term cultures (Fig. 4A)
. Note that the mean GFP fluorescence of these cells was 46 times that of cells transduced with wild-type AML1-ETO (Fig. 4A)
. Moreover, the mean fluorescence of cells expressing the NH2 and NH4 mutants, although higher than the wild type as discussed above, were 6–15-fold lower than that of the cells expressing the AML1 DNA-binding domain alone, consistent with the conclusion that these mutants did not function by passive competition. Thus, both NH2 and NH4 are required for maximal activity of AML1-ETO. Western blot analysis confirmed that AML1 1–177(1–177) is expressed and that levels are far greater than that of AML1-ETO (Fig. 4B)
. The AML1 NH2/NH4 mutant might have been expected to promote self-renewal by the passive mechanism but could not be expressed at this high level (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This is likely because of important biological differences between cell types, e.g., multimerization of AML1-ETO with ETO family members is likely to be a significant factor that enhances repression by AML1-ETO (16
, 21
, 34, 35, 36)
, but C33A cells, e.g., in which the NH2 domain is insufficient for repression, do not express endogenous ETO (11)
. HEL cells provide another example of a cell-specific corepressor environment, as endogenous HDAC2 but not HDAC1 is associated with endogenous ETO (31)
. This property of these cells is quite unusual, as biochemical purifications of corepressor complexes from HeLa cells routinely show HDAC1 and HDAC2 to copurify (40
, 48, 49, 50, 51)
. These cell-specific attributes underscore the importance of the present studies that are performed in primary bone marrow cells, which better reflect the cells of origin of leukemic blasts transformed by AML1-ETO. The data presented here suggest that the NH2 and NH4 domains of ETO in the context of AML1-ETO provide cooperative activity in assays of proliferation, differentiation, and self-renewal.
AML1-ETO Inhibits Both Differentiation and Proliferation of Primary Bone Marrow Cells.
We have shown that cells acutely transduced with AML1-ETO do not differentiate when treated with G-CSF. These cells also cycle less quickly than those transduced with GFP alone. These findings are consistent with recent data showing that AML1-ETO can inhibit both differentiation and proliferation of hematopoietic cells (14
, 15
, 28
, 29)
.
This balance between inhibition of differentiation and proliferation likely occurs in the clinical setting as well. Patients with leukemia in remission can carry the t(8;21) for years while displaying a morphologically normal bone marrow (52, 53, 54, 55) and nonleukemic hematopoietic stem cells carrying the t(8;21) decrease over time in patients in remission (52) . The ability of AML1-ETO to slow proliferation likely helps to check the selective advantage that would otherwise be anticipated in cells with a reduced capacity to differentiate. Mutations complementary to the t(8;21) would be anticipated to lead to relapse by favoring the differentiation block over the proliferation block. Although expression of AML1-ETO slows the proliferation of primary bone marrow cells, transduced cells expressing AML1-ETO can be maintained in long-tem cultures (22, 23, 24, 25, 26) . Indeed, the cells from these cultures morphologically resemble blasts and have a Lin-kit+ surface marker profile, consistent with immature cells. These primary cells expressing AML1-ETO can be passaged beyond 12 weeks in suspension culture when supplemented with appropriate cytokines, consistent with observations made by others (24 , 25 , 27) .
Structure Function Analysis of AML1-ETO in Primary Bone Marrow Cells.
AML1-ETO can inhibit cell cycle progression, inhibit differentiation, and promote long-term expansion of primary bone marrow cells. This system provides an opportunity to evaluate the effects of AML1-ETO mutations on all of these effects. We have focused on the NH2 and NH4 regions that have been implicated in corepressor recruitment. Remarkably, the effects of NH2 and NH4 mutations, alone or in combination, were quite similar whether the measured outcome was inhibition of proliferation, inhibition of differentiation, or extension of self-renewal. In all cases, the NH2/NH4 double mutants were unable to produce the functional consequences associated with AML1-ETO. This strongly suggests that the corepressor recruitment function that is abrogated in the NH2/NH4 mutant is required for all of these activities of wild-type AML1-ETO. By contrast, the single mutations were uniformly able to mimic the functions of AML1-ETO in proliferation, differentiation, and self-renewal; although by some measures, they were less efficient at producing the phenotype. These data suggest that the NH2 and NH4 domains of AML1-ETO are functionally cooperative in primary bone marrow cells.
Previous studies in other selected cell types and immortalized cell lines have found that mutation of either NH2 or NH4 could independently eliminate the activity of AML1-ETO (Table 1)
. Our finding that the deletion of NH2 and NH4 independently produces small effects in primary bone marrow cells underscores the importance of studying the structure function relationships of AML1-ETO in cell types most relevant to its biological target. In addition, although numerous corepressor interaction surfaces exist outside of the NH domains (11
, 34)
, the correlation of loss-of-function with specific loss of NH2 and NH4 domains implies that these are not sufficient for AML1-ETO function in primary bone marrow cells. The specific HDACs and other potential N-CoR/SMRT-associated proteins that are functionally relevant for AML1-ETO-dependent phenotypes in primary bone marrow cells remain to be elucidated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grants HL04339 from the National Heart, Lung, and Blood Institute (to B. A. H.) and DK45586 from the National Institute of Diabetes and Digestive and Kidney Diseases (to M. A. L.). 
2 Present address: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10021.
3 To whom requests for reprints should be addressed, at University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Boulevard, Philadelphia, PA 19104-6149. Phone: (215) 898-0198; Fax: (215) 898-5408; E-mail: lazar{at}mail.med.upenn.edu
4 The abbreviations used are: AML, acute myeloid leukemia; NH, Nervy homology; FACS, fluorescence-activated cell sorter; HDAC, Histone deacetylase; GFP, Green fluorescent protein; G-CSF, granulocyte colony-stimulating factor.
Received 12/17/01. Accepted 4/ 1/02.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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