title: The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling.
abstract: Homeobox genes play a critical role in embryonic development, but they have also been implicated in cancer through mechanisms that are largely unknown. While not expressed during normal T-cell development, homeobox transcription factor genes can be reactivated via recurrent chromosomal rearrangements in human T-cell acute leukemia/lymphoma (T-ALL), a malignancy often associated with activated Notch and Akt signaling. To address how epigenetic reprogramming via an activated homeobox gene might contribute to T-lymphomagenesis, we investigated a transgenic mouse model with thymocyte-specific overexpression of the Dlx5 homeobox gene. We demonstrate for the first time that Dlx5 induces T-cell lymphomas with high penetrance. Integrated ChIP-seq and mRNA microarray analyses identified Notch1/3 and Irs2 as direct transcriptional targets of Dlx5, a gene signature unique to lymphomas from Lck-Dlx5 mice as compared to T-cell lymphomas from Lck-MyrAkt2 mice, which were previously reported by our group. Moreover, promoter/enhancer studies confirmed that Dlx5 directly transactivates Notch expression. Notch1/3 expression and Irs2-induced Akt signaling were upregulated throughout early stages of T-cell development, which promoted cell survival during β-selection of T lymphocytes. Dlx5 was required for tumor maintenance via its activation of Notch and Akt, as tumor cells were highly sensitive to Notch and Akt inhibitors. Together, these findings provide unbiased genetic and mechanistic evidence that Dlx5 acts as an oncogene when aberrantly expressed in T cells, and that it is a novel discovery that Notch is a direct target of Dlx5. These experimental findings provide mechanistic insights about how reactivation of the Dlx5 gene can drive T-ALL by aberrant epigenetic reprogramming of the T-cell genome.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Yinfei
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sementino
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Ito
authors.affiliation: Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Peri
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Dlx5; Notch; T cell lymphoma; homeobox