A Novel Recurrent Chromosomal Inversion Implicates the Homeobox Gene<i>Dlx5</i>in T-Cell Lymphomas from Lck-Akt2 Transgenic Mice

Tan, Yinfei; Timakhov, Roman A.; Rao, Mamta; Altomare, Deborah A.; Xu, Jiawen; Liu, Zemin; Gao, Qingshen; Jhanwar, Suresh C.; Cristofano, Antonio Di; Wiest, David L.; Knepper, Janice E.; Testa, Joseph R.

doi:10.1158/0008-5472.can-07-3218

Cited by 33 publications

(63 citation statements)

References 18 publications

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“…The rag2:myr-mAkt2 construct was generated by placing a myristoylated murine Akt2 transgene (19), which is constitutively activated as a result of constitutive membrane localization, downstream of a zebrafish rag2 promoter fragment (25) in a modified pBluescript vector, wherein the rag2:myr-mAkt2 construct is flanked by recognition sequences for I-SceI meganuclease.…”

Section: Methodsmentioning

confidence: 99%

Aberrant AKT activation drives well-differentiated liposarcoma

Gutiérrez

Snyder

Mariño-Enríquez³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.L iposarcoma is the most common sarcoma of humans, affecting ∼2,000 individuals per year in the United States (1). These tumors are classified into five histopathologic subtypes, with well-differentiated liposarcoma (WDLPS) accounting for ∼50% of cases, and dedifferentiated liposarcoma (DDLPS), a closely related subtype that appears to arise from further malignant progression of WDLPS, accounting for an additional 9% to 18% of cases (1-3). Liposarcomas are generally thought to arise de novo rather than from preexisting benign lesions, and most patients lack recognized causative factors. Although complete surgical resection can be curative, WDLPS often develops in deep anatomic locations, such as the retroperitoneum or mediastinum, where its propensity to enwrap vital structures typically makes complete surgical resection difficult or impossible, leading to high morbidity and mortality rates (1, 4). Radiation and chemotherapy have limited efficacy in the treatment of WDLPS (5, 6). Indeed, there are no systemic therapeutic regimens known to improve survival when complete surgical resection is not feasible, underscoring the need for an improved molecular understanding of WDLPS to stimulate the development of effective targeted therapies.The MDM2-p53 pathway plays a prominent role in WDLPS pathogenesis, with the vast majority of human tumors harboring either MDM2 amplifications or p53 mutations (6-10). Moreover, individuals with germ-line p53 mutations appear to be at increased risk of WDLPS development at a very young age (11).Regions of chromosome 12q13...

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Section: Methodsmentioning

confidence: 99%

Aberrant AKT activation drives well-differentiated liposarcoma

Gutiérrez

Snyder

Mariño-Enríquez³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…2 In some Lck-Myr-Akt2 founder lines, a recurrent chromosomal inversion implicated the homeobox gene Dlx5 as an oncogene. 3 In subsequent work (manuscript in preparation), we found that transgenic Lck-Dlx5 mice develop spontaneous thymic lymphomas that acquire constitutive activation of Akt, due to loss of Pten expression, as well as up regulation of Myc. Such genetic and epigenetic changes are characteristics of other acute T-cell lymphoma animal models as well as human T-ALLs.…”

Section: Discussionmentioning

confidence: 89%

“…2 Tumors from these transgenic mice consistently harbor one or the other of 2 recurrent chromosomal rearrangements that each involve somatic juxtaposition of a T cell receptor (TCR) enhancer and a transcription factor gene, either Dlx5 or Myc -in each case resulting in unregulated expression of Myc protein. 3 Myc is thought to be essential to T cell development, and Myc-null T cells fail to proliferate at the CD4/CD8 double-negative stage in mice. 4 While overexpression of Myc drives T-ALL in zebrafish, transgenic mice specifically overexpressing Myc in immature T cells, under the control of an Lck promoter, did not develop T-ALL, indicating that Myc is necessary, but not sufficient, to induce T-cell malignancy in mice.…”

Section: Introductionmentioning

confidence: 99%

Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice

Tan¹,

Sementino

Pei

et al. 2015

Cancer Biology & Therapy

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Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (0.5 mM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (0.5 mM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.

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“…27 In addition, a recent study has found that a gene crucial for embryonic development can quickly become a potent cancer promoter in adult mice following a genetic misalignment, indicating that embryonic genes can become cancer inducers. 47 Although Oct-4 is normally expressed in embryonic stem cells and germ cells, and it is required for maintaining their pluripotency, it can also promote tumorigenesis when expressed inappropriately. 22,23,27,29 In addition, Oct-4 is expressed in human tumors, including testicular germ cell tumor and breast carcinoma, and it plays a part in human cancer development.…”

Section: Discussionmentioning

confidence: 99%

Mutation in the DNA‐binding domain of the EWS‐Oct‐4 oncogene results in dominant negative activity that interferes with EWS‐Oct‐4‐mediated transactivation

Kim

Lee

Kim

et al. 2009

Intl Journal of Cancer

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The EWS‐Oct‐4 protein is a chimeric molecule in which the amino terminal domain (NTD) of the EWS becomes fused to the carboxy terminal domain (CTD) of the Oct‐4 transcription factor. It was identified in human bone and soft‐tissue tumors associated with t(6;22)(p21;q12). Using in vitro and in vivo systems, we found that the EWS‐Oct‐4 protein self‐associates. The major domains required for self‐association mapped to the EWS NTD (amino acids 70–163) and the POU DNA‐binding domain. EWS‐Oct‐4 protein also associated with EWS‐Oct‐4 (V351P), which contains a mutation in the POU DNA‐binding domain. Using electrophoretic mobility shift assays, we found that the EWS‐Oct‐4 (V351P) mutant interfered with wild‐type EWS‐Oct‐4 DNA‐binding activity. In addition, we found that EWS‐Oct‐4‐mediated transcriptional activation was inhibited by EWS‐Oct‐4 (V351P) protein in vivo. Thus, this mutation in the POU DNA‐binding domain results in a dominant negative protein. These findings suggest that the biological functions of the EWS‐Oct‐4 oncogene can be modulated by the dominant negative mutant EWS‐Oct‐4 (V351P). © 2008 Wiley‐Liss, Inc.

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A Novel Recurrent Chromosomal Inversion Implicates the Homeobox GeneDlx5in T-Cell Lymphomas from Lck-Akt2 Transgenic Mice

Cited by 33 publications

References 18 publications

Aberrant AKT activation drives well-differentiated liposarcoma

Aberrant AKT activation drives well-differentiated liposarcoma

Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice

Mutation in the DNA‐binding domain of the EWS‐Oct‐4 oncogene results in dominant negative activity that interferes with EWS‐Oct‐4‐mediated transactivation

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