Oncogenes, Fusion Genes and Tumor Suppressor Genes

Overexpression of survivin initiates hematologic malignancies in vivo

Abstract

Survivin is an inhibitor of apoptosis protein family member that has an essential role in cellular proliferation as a component of the chromosome passenger complex. Survivin is highly expressed in embryos and in proliferating adult tissues, but it is not expressed in most differentiated cells. During tumorigenesis, however, survivin expression is dramatically upregulated. Although many studies have shown that survivin is required for cancer cells, the extent to which survivin contributes to the initiation of tumors is unknown. Here we show that transgenic mice that overexpress survivin in hematopoietic cells are at an increased risk of hematologic tumors. In examining how survivin might contribute to tumorigenesis, we observed that hematopoietic cells engineered to overexpress survivin are less susceptible to apoptosis. We conclude that survivin may promote tumorigenesis by imparting a survival advantage to cells that acquire additional genetic lesions.

Introduction

Survivin, the smallest member of the inhibitor of apoptosis protein family, has long been recognized as a prognostic and diagnostic marker of various cancers, as it is expressed at very low levels in most adult tissues, but elevated in tumors. High levels of survivin have been observed in many types of solid tumors, such as lung, ovarian, breast, gastric, prostate and pancreatic cancers.1 Overexpression of survivin is shared by hematological malignancies, including acute leukemias, anaplastic and diffuse large cell lymphoma, myelodysplastic syndromes, myeloma and a variety of pediatric blood cancers.2, 3, 4, 5, 6, 7

Survivin is a member of inhibitor of apoptosis protein family, but whether it acts to inhibit apoptosis is controversial. Although several studies have suggested that survivin inhibits apoptosis (for example, Altieri8), other reports have shown that cells lacking survivin die from mitotic catastrophe, the inability to complete mitosis.9 Indeed, an essential role for survivin in cytokinesis has been well defined. Survivin associates with Aurora B kinase, inner centromere protein, and Borealin to form the chromosome passenger complex, which actively participates in mitosis.10, 11 Although survivin is expressed in a cell cycle-dependent manner in normal proliferating cells, it is expressed in a cell cycle-independent manner in cancer cells, suggesting that its high expression in tumors is not merely a consequence of the proliferative index.12

Survivin is required for primitive hematopoiesis, proliferation and/or survival of hematopoietic stem and progenitor cells, erythroid cells, T-cells and activated neutrophils.13, 14, 15, 16, 17, 18 Moreover, survivin is necessary for proliferation and acute leukemia induced by expression of the internal tandem duplication of FLT3.19 The role of survivin in the early stages of hematopoietic neoplasms, however, has not been addressed. To determine whether overexpression of survivin is an initiating event in leukemia, we treated transgenic mice that overexpress survivin (GATA1-Sur) with the DNA alkylating agent, N-ethyl-nitrosourea (ENU). Here, we report that GATA1-Sur mice develop hematologic malignancies at an increased rate and with shorter latency than wild-type littermates. Furthermore, we show that splenocytes from transgenic mice, as well as primary T cells engineered to overexpress survivin, exhibit modest reductions in spontaneous and induced apoptosis. Our results suggest that increased expression of survivin contributes to transformation of hematopoietic cells by promoting a subtle survival advantage.

Materials and methods

Mice

GATA1-Sur mice, which express survivin under the control of the GATA-1 promoter, have been reported.20 Cohorts of transgenic and non-transgenic CD1 littermates were treated with a single intraperitoneal injection of ENU (100 mg/kg) at 1 month of age. Peripheral blood counts were determined using a HemVet950 (Drew Scientific, Oxford, CT, USA). Balb/C mice were purchased from Jackson laboratories. Animal studies were approved by the Northwestern University IACUC.

Flow cytometry

Single cell suspensions of bone marrow and spleen cells were incubated with various lineage specific antibodies and processed as described.21 Flow data were acquired with an LSRII flow cytometer (BD Biosciences, San Diego, CA, USA) and analyzed with FlowJo software (TreeStar, Ashland, OR, USA). Cell cycle and apoptosis of primary splenocytes from wild-type and transgenic animals were measured as described.22

Primary murine T cell experiments

T cells were enriched from spleens of BALB/c mice using EasySep negative selection mouse T-cell enrichment kit (Stem Cell Technologies, Vancouver, Canada) and plated onto anti-mouse CD3e antibody (eBioscience, San Diego, CA, USA, clone 145-2C11) coated 12-well plates along with 5 μg/ml anti-mouse CD28 antibody (eBioscience, San Diego, CA, USA, clone 37.51) for stimulation. After 24 h, cells were transduced with MIGR1 (encoding green fluorescent protein (GFP) alone) or MIGR1-Survivin (encoding Survivin and GFP) retroviruses and were incubated at 37°C under stimulation conditions. For proliferation assays, T cells were labeled with cell trace violet (Invitrogen, Carlsbad, CA, USA) 24 h after viral transduction and the GFP positive cells were analyzed by flow cytometry for proliferation 24, 48 and 72 h later. To test for susceptibility of these cells to apoptosis 24 h after transduction, the cells were treated with drugs for 6–8 h and stained with annexin V-cy5 (Biovision, Mountain View, CA, USA) and SytoX Blue (Invitrogen) and analyzed by flow cytometry. Cell lysates were prepared at 48 h after transduction for western blot analysis.

Histology

Tissues were fixed and processed by standard protocols. Slides were photographed at × 200 or × 400 original magnification on a DM 4000B microscope with a DFC320 camera and captured with DFC Twain software version 6.6.0 (Leica Microsystems, Ltd., Heerbrugg, Switzerland).

Statistical analysis

Evaluation of differences in lifespan was performed with the Log rank (Mantel–Cox) test. The Student's t-test (two-sided, equal variance) was used to compare apoptosis in control and survivin overexpressing primary T cells and in control versus transgenic splenocytes.

Results

We previously generated transgenic mice that express full-length human survivin complementary DNA under the control of the GATA-1 promoter (GATA1-Sur mice) and demonstrated that survivin was upregulated in both the erythroid and megakaryocyte lineages.20 Multiple reports have shown that expression driven by this GATA-1 promoter construct (Figure 1a) is not restricted to erythroid cells and megakaryocytes, but is active more widely in hematopoietic cells.23, 24, 25 Indeed, quantitative RT–PCR analysis revealed that survivin messenger RNA was elevated two- to threefold in B and T cells of transgenic mice as compared with controls (data not shown). Moreover, western blot analysis revealed that survivin expression was markedly upregulated in bone marrow and spleen cells of transgenic mice (Figure 1b).

Figure 1
figure1

ENU-treated GATA1-Survivin transgenic mice are at increased risk of hematologic malignancies. (a) Schematic of the GATA1-Sur transgene construct. (b) Western blot of survivin expression in bone marrow (BM), spleen (Spl), thymus (Thy) and lymph node (LN) of GATA1-Sur transgenic mice and wild-type littermates. Hsc70 was used as a loading control. (c) Survival analysis revealed that ENU-treated GATA1-Sur transgenic mice (TG) had a significantly accelerated disease progression as compared with ENU-treated wild-type littermates (WT). (d) Hematopoietic indices and body and spleen weights of two representative transgenic mice (356 and 315) and their respective controls (338 and 329).

Overexpression of survivin in GATA1-Sur mice did not alter erythroid/megakaryocyte development or lead to spontaneous tumor formation.20 To investigate whether overexpression of survivin contributes to initiation of tumorigenesis and cooperates with secondary mutations to cause disease, we treated GATA1-Sur transgenic mice and non-transgenic littermates with ENU. Mice were monitored on a regular basis by observation and measurement of body weight and routine analysis of complete blood counts. Animals were killed when body weight loss reached 20% or when peripheral blood counts indicated the presence of a hematological malignancy. Analysis of the survival data revealed that there was a significantly shorter latency for development of hematologic malignancies in the transgenic mice as compared with the wild-type littermates (Figure 1c). Within 1 year, 8 of 21 transgenic, but only 1 of 20 wild-type littermates developed disease and were euthanized. Moreover, the spectrum of disease that developed in the transgenic mice differed from that observed in non-transgenic mice. Whereas only one of the wild-type littermates developed a solid tumor at 47 weeks of age, all of the survivin transgenic mice that became sick presented with lymphoma. Three of the transgenic mice developed high-grade lymphoma with prominent tumor infiltration of the bone marrow, spleen, liver and thymus. The disease in these animals (group A, exemplified by mouse 356) was accompanied by marked splenomegaly, elevated white blood cell count, anemia and thrombocytopenia (Figure 1d). In contrast, five transgenic animals developed lymphoma that was not accompanied by splenomegaly or significant changes in peripheral blood counts (group B, exemplified by mouse 315).

Analysis of stained histological sections revealed the presence of high-grade aggressive tumor in the thymus with involvement of the bone marrows and infiltration into the spleens and liver of mice from group A (for example, 356, Figure 2). These tumors were comprised of intermediate to large cells with a fine vesicular chromatin, high mitotic activity and conspicuous cellular debris—all indicative of a high cellular turnover. The second group of diseased animals displayed thymic involvement by tumor that was cytomorphologically identical to the mice in group A. However, the bone marrow and spleen in these mice demonstrated excessive hematopoiesis, including an abundance of erythroid and megakaryocytic precursors in the bone marrow and spleen, but no tumor cells in these organs (for example, 315, Figure 2). Moreover, there was no infiltration of the liver. Western blotting confirmed that survivin was highly expressed in the spleens of diseased mice (Figure 3).

Figure 2
figure2

GATA1-Sur mice develop high-grade lymphoma upon ENU treatment. Hematoxylin and eosin stained sections of sternum bone marrow, spleen, liver and thymus show the presence of high-grade, aggressive lymphoma in one group of mice (e.g. mouse 356). A second set of animals (e.g. mouse 315) displayed lymphoma that was restricted to thymus and was accompanied by myeloproliferation in bone marrow and spleen.

Figure 3
figure3

Survivin is highly expressed in spleens of diseased transgenic animals. The extent of survivin overexpression in tissues from diseased ENU-treated transgenic mice was analyzed by western blot analysis. Mouse 338, non-transgenic control; Mice 356, 351 and 315, diseased GATA1-Sur transgenics. Hsc70 was used as a loading control.

We next, performed immunophenotyping of cells collected from the spleen, bone marrow and thymus of diseased transgenic and control mice. In both groups of animals the tumor cells did not express any of the myeloid antigens evaluated (data not shown). Flow cytometry confirmed the presence of an aberrant population of T cells in the bone marrow and spleen of animal 356 (Figure 4a). These cells consistently expressed CD8, with a subset co-expressing CD4. In contrast, consistent with the histology, we failed to detect appreciable numbers of T cells within the bone marrows and spleens of group B mice. However, analysis of T cells within the thymus of mouse 315 revealed a prominent shift in the immunophenotype of this lineage; the majority of cells in the diseased mice stained for CD4, but not CD8 (Figure 4b). Taken together, these results indicate that all of the diseased survivin transgenic mice developed morphologically aggressive tumors that were derived from T-cells. The difference in the peripheral phenotype of the tumors in the two groups of animals may reflect the different stages of the same malignant process.

Figure 4
figure4

Flow cytometry reveals aberrant lymphoid proliferation in GATA1-Sur diseased mice. Single cell suspensions of bone marrow, spleen and thymus of diseased GATA1-sur mice and control littermates were stained with anti-CD4 and anti-CD8 antibodies. (a) Animal 356 showed an aberrant expansion of T cells in the bone marrow and spleen. (b) Animal 315 showed a localized expansion of abnormal T cells in the thymus, but no evidence of lymphoma in the spleen or bone marrow.

To investigate whether the secondary events caused by ENU occurred in known lymphoma or leukemia oncogene or tumor suppressors, we sequenced Notch1 (HD and PEST domains), Fbw7, Jak2, and Ikzf1 in spleen samples from diseased animals. We failed to find mutations in these genes in any of the murine tumor samples (data not shown).

As a way to determine how overexpression of survivin contributes to tumor initiation, we assayed the effect of ectopic survivin expression on apoptosis and cell cycle of two relevant cell populations. First, splenocytes collected from GATA1-Sur transgenic mice and wild-type control littermates were cultured ex vivo in the presence of etoposide or bcl-2 inhibitor. Transgenic cells showed a small, but significant, reduction in spontaneous death and apoptosis in response to etoposide (Figure 5a and b). Transgenic cells also showed a slight change in cell cycle parameters: GATA1-Sur splenocytes displayed a small but significant decrease in the proportion of G1 cells when cultured ex vivo (Figure 5c and d).

Figure 5
figure5

Splenocytes from GATA1-Sur transgenic mice show subtle differences in apoptosis and cell cycle progression compared with those of wild-type littermates. (a, b) Splenocytes from GATA1-Suv mice or control littermates were cultured in vitro and treated with etoposide or Bcl2 inhibitor and then assayed for viability by annexin V staining. Representative flow plots (a) and means±s.d. for three experiments (b) are shown. (c, d) Splenocytes were cultured for three hours with BrdU and proliferation was assayed by flow cytometry. Representative flow plots (c) and means±s.d. of three experiments (d) are shown. *P<0.05, ***P=0.008.

Second, splenic T cells were purified from wild-type Balb/C mice, electroporated with a survivin-internal ribosome entry site GFP expression construct or with GFP alone and used for assays of apoptosis and proliferation. Western blot analysis revealed that survivin was overexpressed between two-and fourfold (Figure 6a). To measure the effect of survivin on apoptosis, cells were treated with various inducers of cell death 24 h after transduction. Survivin expressing T cells displayed significantly reduced death in response to a JAK2 inhibitor and a trend towards reduced apoptosis when cultured with an AKT inhibitor or trichostatin A (Figure 6b and c). Separately, aliquots of cells were cultured with cell trace violet 24 h after transduction, and proliferation was evaluated at 24, 48 and 72 h by flow cytometry. We failed to detect any appreciable differences in proliferation of these cells as measured by dye dilution (Figure 6c). Thus, in accord with multiple published studies that describe an anti-apoptotic role for survivin in tumors,8, 26 we conclude that survivin may contribute to tumorigenesis by conferring a subtle survival advantage to cells.

Figure 6
figure6

Overexpression of survivin protects primary T cells from death but does not affect proliferation. (a) Primary murine T cells were activated ex vivo, transduced with control vector MIGR1 or MIGR1-survivin and the extent of survivin expression was assessed by western blot. Hsc70 was used as a loading control. Proteins extracted from two separate experiments are shown. (b, c) Aliquots of cells were treated with various inducers of cell death and assayed for viability by annexin V/sytoX blue staining. Representative flow plots (b) and means±s.d. for three experiments (c) are shown. (d) Aliquots of cells were treated with cell trace violet and the cellular proliferation was evaluated by recording dye levels at 24, 48 and 72 h. **P=0.0005.

Discussion

Although not expressed in most adult tissues, survivin is highly expressed in proliferating cells, such as hematopoietic progenitor cells and erythroid cells. High expression of survivin is also seen in nearly all tumors and is frequently associated with poor prognosis.27 Previous studies to characterize the role of survivin in cancer have primarily focused on its anti-apoptotic activity and on its requirements for continued growth of tumors. Multiple groups have shown that reduction in survivin expression, by anti-sense, knockdown, or pharmacological inhibition of gene expression, disrupts tumor growth. Indeed, survivin has been proposed to be a global target of tumor suppression networks.28 Several anti-survivin therapies, including the peptomimetic sheperdin, transcriptional repressors, antisense and anti-survivin immunotherapy are under investigation as novel anti-cancer therapies.8

Our results suggest that overexpression of survivin may precede the development of hematologic malignancies and facilitate tumor formation. Of note, previous reports have suggested that overexpression of survivin facilitates the development of skin cancer. In one study, keratinocytes that overexpress survivin were shown to exhibit resistance to ultraviolet B-induced apoptosis in vitro and in vivo.29 In another study, keratin 14-survivin transgenic mice were found to show diminished regression of papilloma and increased conversion of papilloma to skin cancer.30 Our study is the first, however, to demonstrate a direct, causal relationship between increased survivin expression and development of hematologic malignancies.

On the basis of the increased susceptibility of GATA1-Sur mice to ENU-induced tumorigenesis, we conclude that survivin contributes to the initiation of neoplastic events. Although altered expression of mitotic regulators, such as survivin's partner aurora-B, increases the risk for carcinogenesis by induction of aneuploidy or tetraploidy,31, 32 our findings suggest that overexpression of survivin may contribute to cancer by promoting increased protection from cell death. The effect on survival conferred by ectopic survivin was modest, consistent with the lack of expansion of any particular hematopoietic lineage in healthy transgenic mice. Such a modest survival advantage, however, could certainly confer increased susceptibility to oncogenesis induced by subsequent genetic mutations. Finally, even though we failed to detect cytogenetic abnormalities in the two T-cell tumors analyzed (data not shown), we cannot rule out the possibility that increased levels of survivin may induce aneuploidy. On the basis of our model that increased expression of survivin can facilitate tumor development, quantification of survivin expression in peripheral blood cells maybe a useful biological marker for hematological malignancies.

References

  1. 1

    Fukuda S, Pelus LM . Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 2006; 5: 1087–1098.

    CAS  Article  Google Scholar 

  2. 2

    Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J et al. Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 2000; 96: 1921–1925.

    CAS  PubMed  Google Scholar 

  3. 3

    Cong XL, Han ZC . Survivin and leukemia. Int J Hematol 2004; 80: 232–238.

    CAS  Article  Google Scholar 

  4. 4

    Schlette EJ, Medeiros LJ, Goy A, Lai R, Rassidakis GZ . Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma. J Clin Oncol 2004; 22: 1682–1688.

    CAS  Article  Google Scholar 

  5. 5

    Lopes R, Castro I, Pontes P, Candeias J, Lemoine NR, Sambade C . Expression profile of survivin in acute leukaemias: the importance of differential splicing. Leukemia 2005; 19: 1284–1286.

    CAS  Article  Google Scholar 

  6. 6

    Fangusaro JR, Caldas H, Jiang Y, Altura RA . Survivin: an inhibitor of apoptosis in pediatric cancer. Pediatr Blood Cancer 2006; 47: 4–13.

    Article  Google Scholar 

  7. 7

    Romagnoli M, Trichet V, David C, Clement M, Moreau P, Bataille R et al. Significant impact of survivin on myeloma cell growth. Leukemia 2007; 21: 1070–1078.

    CAS  Article  Google Scholar 

  8. 8

    Altieri DC . Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8: 61–70.

    CAS  Article  Google Scholar 

  9. 9

    Okada H, Mak TW . Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004; 4: 592–603.

    CAS  Article  Google Scholar 

  10. 10

    Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL et al. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol 2000; 10: 1319–1328.

    CAS  Article  Google Scholar 

  11. 11

    Ruchaud S, Carmena M, Earnshaw WC . The chromosomal passenger complex: one for all and all for one. Cell 2007; 131: 230–231.

    CAS  Article  Google Scholar 

  12. 12

    Lu CD, Altieri DC, Tanigawa N . Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 1998; 58: 1808–1812.

    CAS  PubMed  Google Scholar 

  13. 13

    Fukuda S, Pelus LM . Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis. Blood 2001; 98: 2091–2100.

    CAS  Article  Google Scholar 

  14. 14

    Xing Z, Conway EM, Kang C, Winoto A . Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis. J Exp Med 2004; 199: 69–80.

    CAS  Article  Google Scholar 

  15. 15

    Okada H, Bakal C, Shahinian A, Elia A, Wakeham A, Suh WK et al. Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death. J Exp Med 2004; 199: 399–410.

    CAS  Article  Google Scholar 

  16. 16

    Altznauer F, Martinelli S, Yousefi S, Thurig C, Schmid I, Conway EM et al. Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J Exp Med 2004; 199: 1343–1354.

    CAS  Article  Google Scholar 

  17. 17

    Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD . Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med 2007; 204: 1603–1611.

    CAS  Article  Google Scholar 

  18. 18

    Ma AC, Chung MI, Liang R, Leung AY . The role of survivin2 in primitive hematopoiesis during zebrafish development. Leukemia 2009; 23: 712–720.

    CAS  Article  Google Scholar 

  19. 19

    Fukuda S, Singh P, Moh A, Abe M, Conway EM, Boswell HS et al. Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3. Blood 2009; 114: 394–403.

    CAS  Article  Google Scholar 

  20. 20

    McCrann DJ, Yezefski T, Nguyen HG, Papadantonakis N, Liu H, Wen Q et al. Survivin overexpression alone does not alter megakaryocyte ploidy nor interfere with erythroid/megakaryocytic lineage development in transgenic mice. Blood 2008; 111: 4092–4095.

    CAS  Article  Google Scholar 

  21. 21

    Kirsammer G, Jilani S, Liu H, Davis E, Gurbuxani S, Le Beau MM et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 2008; 111: 767–775.

    CAS  Article  Google Scholar 

  22. 22

    Huang Z, Dore LC, Li Z, Orkin SH, Feng G, Lin S et al. GATA-2 reinforces megakaryocyte development in the absence of GATA-1. Mol Cell Biol 2009; 29: 5168–5180.

    CAS  Article  Google Scholar 

  23. 23

    Visvader JE, Fujiwara Y, Orkin SH . Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev 1998; 12: 473–479.

    CAS  Article  Google Scholar 

  24. 24

    Jasinski M, Keller P, Fujiwara Y, Orkin SH, Bessler M . GATA1-Cre mediates Piga gene inactivation in the erythroid/megakaryocytic lineage and leads to circulating red cells with a partial deficiency in glycosyl phosphatidylinositol-linked proteins (paroxysmal nocturnal hemoglobinuria type II cells). Blood 2001; 98: 2248–2255.

    CAS  Article  Google Scholar 

  25. 25

    Hock H, Meade E, Medeiros S, Schindler JW, Valk PJ, Fujiwara Y et al. Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev 2004; 18: 2336–2341.

    CAS  Article  Google Scholar 

  26. 26

    Altieri DC . Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 2003; 22: 8581–8589.

    CAS  Article  Google Scholar 

  27. 27

    Fulda S . Inhibitor of apoptosis proteins in hematological malignancies. Leukemia 2009; 23: 467–476.

    CAS  Article  Google Scholar 

  28. 28

    Guha M, Altieri DC . Survivin as a global target of intrinsic tumor suppression networks. Cell Cycle 2009; 8: 2708–2710.

    CAS  Article  Google Scholar 

  29. 29

    Grossman D, Kim PJ, Blanc-Brude OP, Brash DE, Tognin S, Marchisio PC et al. Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clin Invest 2001; 108: 991–999.

    CAS  Article  Google Scholar 

  30. 30

    Allen SM, Florell SR, Hanks AN, Alexander A, Diedrich MJ, Altieri DC et al. Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. Cancer Res 2003; 63: 567–572.

    CAS  PubMed  Google Scholar 

  31. 31

    Nguyen HG, Makitalo M, Yang D, Chinnappan D, St Hilaire C, Ravid K . Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J 2009; 23: 2741–2748.

    CAS  Article  Google Scholar 

  32. 32

    Nguyen HG, Ravid K . Tetraploidy/aneuploidy and stem cells in cancer promotion: The role of chromosome passenger proteins. J Cell Physiol 2005; 208: 12–22.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Todd Yezefski for initiating these studies and Hui Liu and Jeremy Wen for assistance with animal colony maintenance. This work was supported, in part, by a Grant from the NIH (DK074693). JDC is a Scholar of the Leukemia and Lymphoma Society.

Author information

Affiliations

Authors

Corresponding author

Correspondence to J D Crispino.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Small, S., Keerthivasan, G., Huang, Z. et al. Overexpression of survivin initiates hematologic malignancies in vivo. Leukemia 24, 1920–1926 (2010). https://doi.org/10.1038/leu.2010.198

Download citation

Keywords

  • neoplasia
  • survivin
  • apoptosis

Further reading

Search

Quick links