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Journal of Virology, February 2004, p. 1971-1980, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1971-1980.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Large-Scale Identification of Disease Genes Involved in Acute Myeloid Leukemia

Stefan J. Erkeland, Marijke Valkhof, Claudia Heijmans-Antonissen, Antoinette van Hoven-Beijen, Ruud Delwel, Mirjam H. A. Hermans, and Ivo P. Touw*

Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

Received 7 July 2003/ Accepted 27 October 2003


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ABSTRACT
 
Acute myeloid leukemia (AML) is a heterogeneous group of diseases in which chromosomal aberrations, small insertions or deletions, or point mutations in certain genes have profound consequences for prognosis. However, the majority of AML patients present without currently known genetic defects. Retroviral insertion mutagenesis in mice has become a powerful tool for identifying new disease genes involved in the pathogenesis of leukemia and lymphoma. Here we have used the Graffi-1.4 strain of murine leukemia virus, which causes predominantly AML, in a screen to identify novel genes involved in the pathogenesis of this disease. We report 79 candidate disease genes in common integration sites (CISs) and 15 genes whose family members previously were found to be affected in other studies. The majority of the identified sequences (60%) were not found in lymphomas and monocytic leukemias in previous screens, suggesting a specific involvement in AML. Although most of the virus integrations occurred in or near the 5' or 3' ends of the genes, suggesting deregulation of gene expression as a consequence of virus integration, 18 CISs were located exclusively within the genes, conceivably causing gene disruption.


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INTRODUCTION
 
Acute myeloid leukemia (AML) is characterized by a block in myeloid differentiation that results in the accumulation of leukemic myeloid cells in the bone marrow and peripheral blood. For AML cases with specific chromosomal translocations, the identification and functional characterization of fusion genes located at translocation breakpoints have resulted in the discovery of pathways involved in leukemic transformation (34). However, it also has become clear that these defects themselves are not sufficient to cause acute leukemia, supporting the theory that the disruption of multiple regulatory mechanisms is required to fully transform hematopoietic stem and progenitor cells toward AML. At present, cytogenetic parameters are used successfully in clinics for risk stratification of leukemia. For instance, AML cases with t(8;21), t(15;17), and inv(16) chromosomal abnormalities are classified as low risk, whereas cases with 3q26, 5q, and 7q abnormalities generally are classified as high risk, with unfavorable treatment outcomes resulting in early relapse and decreased overall survival (34, 47). Importantly, for the majority of AML cases (>60%), tentatively classified as intermediate risk, the genetic parameters predictive for therapy outcome have not been identified (14, 15). Furthermore, in the approximately 20 to 40% of AML patients without chromosomal abnormalities, the molecular pathogenesis remains entirely unknown (33).

Retroviral insertion mutagenesis in mice has become a powerful and rapid method for the identification of new genes involved in cancer (23). This approach has benefitted greatly from both human and mouse genome programs and the recently developed genome database search programs (20, 29). Studies aimed at finding novel genes involved in leukemia thus far have been carried out with virus strains that have a propensity to induce lymphoid malignancies or myelomonocytic tumors (21, 26, 32, 37, 44, 54). To focus this strategy on myeloid leukemia, we have used the Graffi-1.4 (Gr-1.4) virus, which has been demonstrated to induce leukemia with predominantly myeloid or mixed-lineage early hematopoietic phenotypes (9, 48). As with the Moloney and Cas-Br-M viruses used in previous studies, the Gr-1.4 virus does not contain oncogenic sequences but can deregulate or disrupt gene expression due to proviral integration.

Recently, Erkeland et al. reported on a new Gr-1.4 virus common integration site (CIS) that is located in the Yin Yang 1 (YY1) promoter and that causes the deregulation of YY1 gene expression, resulting in defective myeloid differentiation (9). Here we report 94 candidate leukemia disease genes that are targeted by the Gr-1.4 virus. While some of the affected genes in the Gr-1.4 virus-induced leukemia overlapped with those identified in lymphoma screens, suggesting a more general involvement in leukemogenesis and lymphogenesis, the majority of integrations appeared to affect novel genes that may be more specifically involved in the development of myeloid malignancies.


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MATERIALS AND METHODS
 
MuLV Gr-1.4-induced leukemia. Newborn mice were injected subcutaneously with 100 µl of cell culture supernatant from murine leukemia virus (MuLV) Gr-1.4-producing NIH 3T3 cells (a gift from E. Rassart, Department des Sciences Biologiques, Universite du Quebec à Montreal, Montreal, Quebec, Canada). Mice were treated and analyzed for the development of leukemia as previously described (9). Chromosomal DNA was isolated from leukemic cells for PCR-based screening (9).

Cytological analysis and immunophenotyping of leukemic cells. For morphological analysis, blood smears and cytospin preparations were fixed in methanol, stained with May-Grünwald-Giemsa stained, and examined by using an Axioscope microscope (Carl Zeiss BV, Weesp, The Netherlands). Single-cell suspensions of different organs were analyzed by flow cytometry with a FACScan flow cytometer (Becton Dickinson and Co., Mountain View, Calif.). Cells were labeled as described previously (25) with the following rat monoclonal antibodies: ER-MP54, ER-MP58, M1/70 (Mac-1), F4/80, RB68C5 (GR-1), ER-MP21 (transferrin receptor), TER119 (glycophorin A), 59-AD2.2 (Thy-1), KT3 (CD3), RA3 6B2 (B220), and E13 161-7 (Sca1). Immunodetection was performed with goat anti-rat antibodies coupled to fluorescein isothiocyanate (Nordic, Tilburg, The Netherlands).

Inverse PCR of MuLV Gr-1.4-induced leukemia. The inverse PCR strategy was recently described in detail (9). Briefly, genomic DNA from primary tumors was digested with HhaI (CGCG). After circularization by ligation (rapid ligation kit; Roche Diagnostics, Mannheim, Germany), an initial PCR was performed with MuLV Gr-1.4 (long terminal repeat [LTR])-specific primers L1 (5'-TGCAAGATGGCGTTACTGTAGCTAG-3') and L2 (5'-CCAGGTTGCCCCAAAGACCTG-3'). Cycling conditions were 1 min at 94°C, 1 min at 62°C, and 3 min at 72°C for 30 cycles. For the second, nested PCR, primers L1N (5'-AGCCTTATGGTGGGGTCTTTC-3') and L2N (5'-AAAGACCTGAAACGACCTTGC-3') (15 cycles) were used. The PCR mixture contained 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 200 µM deoxynucleoside triphosphates, 10 pmol of each primer, and 2.5 U of Taq polymerase (Pharmacia, Uppsala, Sweden). The PCR fragments were analyzed on a 1% agarose gel.

Detection of virus integration by a specific nested PCR. To determine the localization of the Gr-1.4 provirus in specific virus-targeted genes in an extended panel of leukemias, a nested PCR was performed with DNA from primary tumors. For the first PCR, virus integration site locus-specific primers X1 and X2 were used in combination with MuLV Gr-1.4 LTR-specific primers L1 and L2 (Fig. 1). Cycling conditions were 1 min at 94°C, 1 min at 62°C, and 3 min at 72°C for 30 cycles. For the second PCR, nested virus integration site-specific primers X1N and X2N were used in combination with nested LTR-specific primers L1N and L2N under the same conditions (Fig. 1). The PCR products obtained were analyzed by Southern blotting. To verify the correct nature of the amplified bands, the blots were hybridized with radiolabeled gene-specific probes P1 and P2 (Fig. 1) at 45°C in Church buffer (0.5 M phosphate buffer [pH 7.2], 7% [wt/vol] sodium dodecyl sulfate, 10 mM EDTA) overnight. Signals were visualized by autoradiography according to standard procedures (34a).



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  		FIG. 1. Directed PCR of chromosomal DNA to determine the commonality of virus integration sites (VIS) identified by inverse PCR. Primers X1, X1N, X2, and X2N were designed from a locus that was identified as a virus integration site by inverse PCR. To amplify flanking genomic sequences and to determine the localization and orientation of the integrated provirus, four different nested PCRs were performed. First, primers X1 and X2 were combined with MuLV Gr-1.4 LTR primers L1 and L2. The products were amplified by a nested PCR with primers X1N and X2N in combination with L1N and L2N. The specificity of the amplified bands was checked by Southern blot analysis with probes P1 and P2.

Nucleotide sequence analysis. PCR products were sequenced by using an ABI 3100 sequencer (Applied Biosystems, Neuwerkerk aan den Ijssel, The Netherlands) with MuLV Gr-1.4-specific forward primer L1. Virus flanking genomic sequences were analyzed by using GenBank (National Center for Biotechnology Information), a Celera discovery system (Celera Genomics, Rockville, Md.) (19, 29), and Ensembl (Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom) (20).


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RESULTS
 
Gr-1.4-induced leukemias. Eighty-nine newborn FVB/N mice were inoculated with Gr-1.4. When moribund, mice were sacrificed, and hematopoietic organs were isolated. Six mice died without signs of leukemia and were excluded from further investigation. Standard blood cell analysis was performed, and values were compared with the mean value for 10 normal FVB/N mice (24). Most of the leukemic mice had increased numbers of peripheral white blood cells and decreased numbers of platelets and red blood cells compared to normal controls (data not shown). Blast percentages in the bone marrow ranged from 24 to 90%, with an average of 48%. Leukemic cells from 76 mice were immunophenotyped. The major immunophenotypic features of these leukemias are given in Table 1. Based on these criteria, the leukemias were classified as T-lymphoid; mixed lymphoid, erythroid, and myeloid; myeloid; myelomonocytic; or erythroid. Fifty-nine leukemias were analyzed morphologically. Representative examples are shown in Fig. 2. Almost all of the mice showed splenomegaly, with 25% showing thymus enlargement, 20% showing lymph node enlargement, and 55% showing liver involvement. In 5% of the mice, leukemic cells were present in the bone marrow and blood, without overt peripheral organ involvement.


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  		TABLE 1. Gr-1.4-induced leukemiasa



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  		FIG. 2. Morphological features of MuLV Gr-1.4-induced leukemia. Micrographs were taken with a Zeiss Axioscope microscope (magnification, x1,000). Morphological subtypes were lymphoblasts (I); mixed erythroblasts, myeloblasts, and lymphoblasts (II); myeloblasts (III); myelo-monoblasts (IV); and erythroblasts (V).

Virus integration sites in Gr-1.4-induced leukemias. PCR analysis in conjunction with database searches identified a total of 94 different virus integration sites out of 69 tumors, 38 of which were found in earlier screens. Examples of this latter group of CISs are p53 (39, 41), Notch-1 (12, 13, 31), Evi-1 (38), NF1 (Evi-2) (5), Lck-1 (1, 11, 35), Pim-1 (50), HoxA9 (Evi-6) (43), Fli-1 (4, 8), and N-Myc (18, 51). Notably, 79 of the 94 integrations were CISs, directly implicating the affected genes in leukemic transformation. The remaining 15 were included in this report because family members closely related to these genes were found in other studies. Fifty-six of the identified sequences were mapped near or in novel candidate leukemia genes. The products of the affected genes have been classified as receptors and signaling molecules (Table 2), as regulators of transcription (Table 3), and as having regulatory roles in other pathways (e.g., DNA stability and proteasomal targeting) or unknown functions (Table 4).


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  		TABLE 2. MuLV Gr-1.4 integration sites in receptors and signaling-related molecules


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  		TABLE 3. MuLV Gr-1.4 integration sites in transcriptional regulators


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  		TABLE 4. Other MuLV Gr-1.4 integration sites

Approximately 15% of the virus integrations identified by this inverse PCR-based screen were determined to be common (more than two integrations in a particular genomic locus) by the initial screen. To determine the frequency of common integrations more sensitively, we performed integration-specific PCRs with 49 Gr-1.4-targeted genes in multiple tumors (Tables 2 to 4); most appeared to be common. We sequenced the integrations in 19 genes derived from multiple (2 to 10) tumors; these included VDUP1, PrdxII, 11- to 19-lysine-rich leukemia (ELL), promyelocytic leukemia zinc finger (PLZF), and Edg3. In all instances, the integrations were located in the expected gene but at different positions, confirming the specificity of the Southern analysis and ruling out the possibility of cross-contamination by previously amplified PCR products. The genes flanking the virus integration sites were compared with data from the National Cancer Institute retrovirus-tagged cancer gene database (RTCGD) at http://genome2.ncifcrf.gov and other sources (Tables 2 to 4). The Gr-1.4 integrations that are included in this database or that were reported in other studies are indicated by the database name or references in Tables 2 to 4. Family members of Gr-1.4-targeted genes found in other studies are also indicated in those tables. Most of the virus integrations occurred in or near the 5' or 3' ends of the genes, suggesting that the levels of expression of these genes are deregulated as a consequence of virus integration. Eighteen CISs were located exclusively within the gene, conceivably causing gene disruption. This group comprises the previously reported virus targets Notch-1, NF1, PTPN1, Inpp4a, p53, SWAP70, and Kcnk5 and 11 new virus targets: calcyphosine, phosphodiesterase 1, ELL, NCOR-1, HDAC-7A, histone H3.3A, Api-5, Ril, D6Mm5e, and two unknown genes.


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DISCUSSION
 
In this study, we have used in vivo retroviral mutagenesis with the Gr-1.4 virus complex to identify novel disease genes specifically involved in the pathogenesis of AML. In comparable studies with other virus strains, e.g., Moloney, AKXD, or Cas-Br-M, the most prominently appearing tumor types are T- and B-cell lymphomas; in the case of BXH2, myelomonocytic tumors are prominent (21, 30, 32, 37, 54). In contrast, more than 80% of the leukemias induced by Gr-1.4 unequivocally exhibited immunophenotypic characteristics of myeloid cells, with immature morphological features (mainly myeloblasts), emphasizing the unique features of the Gr-1.4 virus complex as a tool for characterizing pathogenetic mechanisms in myeloid disease. Indeed, the majority of the CISs described here have thus far not been reported in extensive screens in lymphoma models, although some overlap was observed. The latter observation is not surprising in view of the fact that cell type-specific events usually impinge on downstream common regulatory pathways that can be affected in multiple tumor types.

Although most of the Gr-1.4 CISs have been linked to candidate disease genes based on their proximity to these genes, proviral integrations have been reported to influence gene expression over distances of more than 100 kb. Thus, we cannot exclude the possibilities that genes located more distantly from the CISs also are deregulated and that multiple genes are affected by a single CIS (44). In addition, three other aspects of retroviral screens as they are currently being performed must be emphasized. First, malignancies induced by replication-competent retroviruses are usually oligo- or polyclonal rather than monoclonal (9, 32). Although this characteristic gives rise to high frequencies of CISs in relatively small cohorts of mice, it complicates the search for cooperating events within one leukemic clone. Second, the sensitive PCR-based techniques used to identify virus integrations do not allow distinction between CISs present in a majority of the leukemic cells, initiating an early pathogenic event, and CISs present in only a minor population of the cells, probably affecting leukemia progression genes. Finally, a recent study emphasized that MuLV strains have a preference for integration near transcriptional start sites (62). Our data obtained with Gr-1.4 corroborate these conclusions and indicate that retroviral mutagenesis with MuLV preferentially, although not exclusively, identifies gene deregulation rather than gene disruption. Another important conclusion drawn by Wu and colleagues is that there appear to be no integration hot spots (preferred integration sites in certain loci) for MuLV (62). Therefore, CISs found in viral screens are likely to play a role in leukemia.

Many of the Gr-1.4-affected genes appeared to be related to signaling; some have been linked to human leukemia already. For instance, the Tie-1 gene, which encodes a tyrosine kinase receptor that is normally expressed in vascular endothelial cells and hematopoietic stem cells, is overexpressed in chronic myeloid leukemia (59). Importantly, high Tie-1 levels inversely correlate with the survival of chronic myeloid leukemia patients in the early chronic phase (59). Markedly increased levels of Tie-1 also were detected in bone marrow samples from myelodysplastic syndrome and AML patients (58). Notch-1 is another example of a CIS associated with human disease. The human homologue of the Notch (Tan-1) gene is involved in chromosomal translocation t(7;9)(q34;34.3), which results in a truncated receptor in human T-lymphoblastic neoplasms. Notch-1 is a proviral integration site in mouse lymphoid leukemias (12, 31). Our data suggest that aberrant Notch signaling also may be involved in myeloid leukemia. Notably, the integrations in the Notch gene result in the constitutive formation of the truncated active form of Notch (31), which has been demonstrated to interfere with granulocyte colony-stimulating factor-induced myeloid differentiation in the 32D cell model (55). Edg3 (endothelial differentiation gene 3) is a G-protein-coupled receptor (GPCR) involved in cell proliferation and survival (2). The expression of Edg3 is downregulated during the differentiation of HL60 human leukemia cells and is assumed to mediate sphingosine 1-phosphate-induced Ca2+ responses (49). Although the role of Edg receptors in normal hematopoiesis and malignancies is not yet clear, a closely related GPCR, cannabinoid receptor type 2, was found in a CIS in Cas-Br-M-induced leukemia (57). Notably, perturbed expression of cannabinoid receptor type 2 recently was found to interfere with myeloid differentiation, supporting the notion that this type of GPCR may contribute to the pathogenesis of AML by inducing a maturation block (27).

Both protein and lipid phosphatases are crucial, mostly negative, regulators in growth factor signaling pathways (7, 64). Two members of the protein tyrosine phosphatase nonreceptor (PTPN) family affected by Gr-1.4 are PTPN1 and PTPN5. The virus integrations in the PTPN1 gene are localized in intron 1 and conceivably disrupt its function. The PTPN1 gene was found in a CIS in BXH2-induced leukemia (32). Because TYK2, JAK2, and STAT5—JAK/STAT signaling intermediates involved in growth control by hematopoietic growth factors—are all inactivated by PTPN1 (also known as PTP1B) (3, 16, 42), the disruption of PTPN1 is predicted to contribute to uncontrolled proliferation and survival of leukemic cells. Integrations in the PTPN5 gene occur in exon 1, upstream of the ATG translation start site. At present, little is known regarding the signaling function of PTPN5, which is alternatively termed STEP. Interestingly, recent data suggest that PTPN5/STEP shows a preferential affinity for p38 mitogen-activated protein kinase in a redox-sensitive manner, leaving the Erk kinases largely unaffected (40). Inhibition of p38 mitogen-activated protein kinase activity by pharmacological inhibitors has been shown to interfere with terminal neutrophilic differentiation (G.-J. van de Geijn et al., unpublished data) and to prevent apoptosis in neutrophils (10). Conceivably, dephosphorylation of p38 by PTPN5/STEP may have similar effects and may promote the survival of immature myeloid cells. Other phosphatases that are targeted by Gr-1.4 are the inositol polyphosphate phosphatases Inpp4a and Inpp5b, which catalyze the hydrolysis of phosphatidylinositol polyphosphates at positions 4 and 5, respectively. Intriguingly, Inpp4a is a major target for transcription factor GATA-1 and inhibits the growth of megakaryocytes and NIH 3T3 fibroblasts (60). Inpp5b is required for normal sperm development and function (17), but how this enzyme affects normal or leukemic blood cell development is not known.

Reactive oxidant species (ROS) are generated by multiple cellular mechanisms, including metabolic processes, phagocytic reponses to pathogens (oxidative burst), and membrane receptor-mediated signaling. The tight regulation of ROS concentrations in the cell is controlled by both catabolic and redox mechanisms and is important for signal transduction, as it influences protein kinase and phosphatase reactions as well as the activities of transcription factors (46). When ROS levels in a cell are too high, the resulting oxidative stress will affect normal protein function and genomic stability (46). Genes involved in the redox-controlled regulation of ROS levels that are commonly targeted by Gr-1.4 are those for vitamin D3-upregulated protein 1 (VDUP1) and peroxiredoxin 2 (PrdxII). VDUP1 interacts with thioredoxin (TRX) and thereby counteracts the ameliorating effects of TRX on stress-induced apoptosis via apoptosis signal-regulating kinase 1 (ASK-1) and the function of TRX as an antioxidant (28). The consequence of upregulation of PrdxII is as yet unclear, but it may interfere with the function of peroxiredoxin complexes and therefore inhibit the antistress activities of TRX (6). Importantly, PrdxII is a TRX reductase and has been found to be overexpressed in human breast cancer (45).

The ELL and PLZF genes are two examples of genes that are part of fusion genes in human AML as a result of chromosomal translocations. In translocation t(11;19)(q23;p13.1), the ELL gene is fused to the trithorax-like mixed lineage leukemia (MLL) gene (56). The ELL protein is an RNA polymerase II elongation factor (53). Recently, it was demonstrated that both MLL-ELL and ELL inhibit p53 activity via binding of the C-terminal part of ELL to the transactivating domain of p53 (61). The PLZF gene, involved in translocation t(11;17)(q23;q21), is fused in frame with RAR{alpha} (22, 36). PLZF is expressed in hematopoietic stem cells and normally is downregulated during differentiation. The overexpression of PLZF plays a role in the maintenance of the immature state of hematopoietic progenitor cells and promotes cell survival (52, 63). The fact that PLZF is found as a common Gr-1.4-targeted gene indicates that the deregulation of PLZF expression can contribute to leukemic development independent of its fusion to RAR{alpha}. One of the major features of PLZF is its tight binding to transcriptional corepressors. Interestingly, several genes involved in transcriptional repression by chromatin modification, such as those for N-Cor-1 and histone deacetylases HDAC1 and HDAC7, are affected by Gr-1.4. Notably, family members of these proteins (N-Cor-2 and HDAC5) also were found in previous screens (54)

In conclusion, using high-throughput retroviral screens with the Gr-1.4 virus complex, we have identified novel pathways involved in myeloid leukemia. Currently, we are studying the consequences of aberrant gene expression or function by using gene transfer methodology with 32D cells and primary bone marrow cultures (9). In addition, we are analyzing the significance of these pathways for human AML by screening expression levels in a panel of clinical samples with a gene expression array and quantitative reverse transcription-PCR technology. By following this combinatorial approach, we hope to develop new prognostic indicators that will discriminate further between low and high responses to therapy in different risk groups. Furthermore, the results obtained may open new avenues for developing specific and sensitive therapies based on the heterogeneous pathogenetic features of human AML.


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ACKNOWLEDGMENTS
 
We thank E. Rassart for providing the cell line that produced MuLV Gr-1.4.

This work was supported by grants from the Dutch Cancer Society Koningin Wilhelminafonds.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Hematology, Erasmus University Medical Center, Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31-10-4087837. Fax: 31-10-4089470. E-mail: i.touw{at}erasmusmc.nl. Back


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Journal of Virology, February 2004, p. 1971-1980, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1971-1980.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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