The Myc oncoprotein is a bHLH-LZ transcription factor that heterodimerizes with another bHLH-LZ protein, Max, in order to bind DNA and activate transcription. Max also dimerizes with alternative bHLH-LZ partners, including Mxd1-4, Mnt and Mga: these proteins act as transcriptional repressors, are thought to counteract Myc activity at common target genes, and may thus conceivably act as tumor suppressors. Consistent with this concept, Small Cell Lung Cancer (SCLC) shows sporadic loss of either Max or Mga, as well as Myc amplification: all of these events are mutually exclusive, pointing to a common functional consequence. At the molecular level, Max and Mga are also part of a variant of the Polycomb Repressive Complex (PRC1.6), the function of which – if any – in tumorigenesis remains to be characterized. Based on the above observations, we hypothesized that Mga/Max dimers may recruit the PRC1.6 complex to chromatin, thereby antagonizing Myc/Max function. We further speculated that this may endow Mga and/or Pcgf6 with widespread tumor suppressor activity, possibly extending to tumor types other than SCLC. Here, we addressed the roles of Pcgf6 and Mga in Eμ-myc transgenic mice, a well- characterized model of Myc-induced lymphomagenesis. Remarkably, B-cell specific deletion of Pcgf6 – but not Mga – led to a marked acceleration in lymphoma onset. As assessed by ChIP- and RNA-seq profiling, loss of Mga or Pcgf6 affected neither DNA-binding by Myc/Max, nor Myc-regulated transcription. Nonetheless, while having no impact tumor onset, deletion of Mga led to a near-complete loss of Pcgf6 recruitment to chromatin, implying that Pcgf6 suppressed lymphomagenesis through an alternative mechanism. Close inspection of mRNA profiles indicated that Pcgf6-null lymphomas were associated with a mild downregulation of genes involved in immune surveillance pathways. Immunophenotypic 9 profiling of infiltrating cells in transplanted lymphomas pointed to a reduction in infiltrating T-cells, and in particular of effector CD8+ and CD4+ T-cells in Pcgf6-null tumors. Altogether, we have shown that Pcgf6 acts as a tumor suppressor in a model of Myc-induced B-cell lymphoma, but does so in a Mga- and PRC1.6-independent manner. While cell- autonomous Pcgf6-dependent effects in lymphoma B-cells remain to be addressed, our data point to a possible non-cell autonomous function of Pcgf6 in T-cell recruitment and/or activation, and thus possibly in tumor rejection.

TUMOR SUPPRESSIVE ROLE OF THE POLYCOMB GROUP RING FINGER PROTEIN PCGF6 IN MYC-INDUCED LYMPHOMAGENESIS / N. Tanaskovic ; supervisor: B. Amati ; added supervisor: A. Bisso. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2020 Jan 28. ((31. ciclo, Anno Accademico 2019.

TUMOR SUPPRESSIVE ROLE OF THE POLYCOMB GROUP RING FINGER PROTEIN PCGF6 IN MYC-INDUCED LYMPHOMAGENESIS

N. Tanaskovic
2020-01-28

Abstract

The Myc oncoprotein is a bHLH-LZ transcription factor that heterodimerizes with another bHLH-LZ protein, Max, in order to bind DNA and activate transcription. Max also dimerizes with alternative bHLH-LZ partners, including Mxd1-4, Mnt and Mga: these proteins act as transcriptional repressors, are thought to counteract Myc activity at common target genes, and may thus conceivably act as tumor suppressors. Consistent with this concept, Small Cell Lung Cancer (SCLC) shows sporadic loss of either Max or Mga, as well as Myc amplification: all of these events are mutually exclusive, pointing to a common functional consequence. At the molecular level, Max and Mga are also part of a variant of the Polycomb Repressive Complex (PRC1.6), the function of which – if any – in tumorigenesis remains to be characterized. Based on the above observations, we hypothesized that Mga/Max dimers may recruit the PRC1.6 complex to chromatin, thereby antagonizing Myc/Max function. We further speculated that this may endow Mga and/or Pcgf6 with widespread tumor suppressor activity, possibly extending to tumor types other than SCLC. Here, we addressed the roles of Pcgf6 and Mga in Eμ-myc transgenic mice, a well- characterized model of Myc-induced lymphomagenesis. Remarkably, B-cell specific deletion of Pcgf6 – but not Mga – led to a marked acceleration in lymphoma onset. As assessed by ChIP- and RNA-seq profiling, loss of Mga or Pcgf6 affected neither DNA-binding by Myc/Max, nor Myc-regulated transcription. Nonetheless, while having no impact tumor onset, deletion of Mga led to a near-complete loss of Pcgf6 recruitment to chromatin, implying that Pcgf6 suppressed lymphomagenesis through an alternative mechanism. Close inspection of mRNA profiles indicated that Pcgf6-null lymphomas were associated with a mild downregulation of genes involved in immune surveillance pathways. Immunophenotypic 9 profiling of infiltrating cells in transplanted lymphomas pointed to a reduction in infiltrating T-cells, and in particular of effector CD8+ and CD4+ T-cells in Pcgf6-null tumors. Altogether, we have shown that Pcgf6 acts as a tumor suppressor in a model of Myc-induced B-cell lymphoma, but does so in a Mga- and PRC1.6-independent manner. While cell- autonomous Pcgf6-dependent effects in lymphoma B-cells remain to be addressed, our data point to a possible non-cell autonomous function of Pcgf6 in T-cell recruitment and/or activation, and thus possibly in tumor rejection.
AMATI, BRUNO
ALCALAY, MYRIAM
MYC; lymphoma; B cells; tumor suppressor
Settore MED/04 - Patologia Generale
TUMOR SUPPRESSIVE ROLE OF THE POLYCOMB GROUP RING FINGER PROTEIN PCGF6 IN MYC-INDUCED LYMPHOMAGENESIS / N. Tanaskovic ; supervisor: B. Amati ; added supervisor: A. Bisso. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2020 Jan 28. ((31. ciclo, Anno Accademico 2019.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/695195
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