RESUMEN
BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
Asunto(s)
Perfilación de la Expresión Génica , Monocitos/metabolismo , Monocitos/patología , Neoplasias de la Próstata/genética , Transcriptoma , Microambiente Tumoral/genética , Biología Computacional/métodos , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Inmunofenotipificación , Estimación de Kaplan-Meier , Masculino , Anotación de Secuencia Molecular , Pronóstico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/mortalidadRESUMEN
The hematopoietically expressed homeobox gene, Hhex, is a transcription factor that is important for development of definitive hematopoietic stem cells (HSCs) and B cells, and that causes T-cell leukemia when overexpressed. Here, we have used an Hhex inducible knockout mouse model to study the role of Hhex in adult hematopoiesis. We found that loss of Hhex was tolerated in HSCs and myeloid lineages, but resulted in a progressive loss of B lymphocytes in the circulation. This was accompanied by a complete loss of B-cell progenitors in the bone marrow and of transitional B-cell subsets in the spleen. In addition, transplantation and in vitro culture experiments demonstrated an almost complete failure of Hhex-null HSCs to contribute to lymphoid lineages beyond the common lymphoid precursor stage, including T cells, B cells, NK cells, and dendritic cells. Gene expression analysis of Hhex-deleted progenitors demonstrated deregulated expression of a number of cell cycle regulators. Overexpression of one of these, cyclin D1, could rescue the B-cell developmental potential of Hhex-null lymphoid precursors. Thus, Hhex is a key regulator of early lymphoid development, functioning, at least in part, via regulation of the cell cycle.
Asunto(s)
Proteínas de Ciclo Celular/genética , Ciclina D1/genética , Hematopoyesis/genética , Proteínas de Homeodominio/genética , Linfopoyesis/genética , Células Precursoras de Linfocitos B/patología , Factores de Transcripción/genética , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Proteínas de Ciclo Celular/inmunología , Diferenciación Celular , Proliferación Celular , Ciclina D1/inmunología , Células Dendríticas/inmunología , Células Dendríticas/patología , Eliminación de Gen , Regulación de la Expresión Génica , Prueba de Complementación Genética , Hematopoyesis/inmunología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Proteínas de Homeodominio/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Recuento de Linfocitos , Depleción Linfocítica , Linfopoyesis/inmunología , Ratones , Ratones Noqueados , Células Precursoras de Linfocitos B/inmunología , Bazo/inmunología , Bazo/patología , Linfocitos T/inmunología , Linfocitos T/patología , Factores de Transcripción/deficiencia , Factores de Transcripción/inmunología , Transcripción GenéticaRESUMEN
Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.
