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Cancer-associated TERT promoter mutations abrogate telomerase silencing.

Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D - Elife (2015)

Bottom Line: We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease.Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity.Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.

No MeSH data available.


Related in: MedlinePlus

Model explaining the tumor spectrum associated with TERT promoter mutations.Shown are the differential outcomes of a cell acquiring a cancer-associated TERT promoter mutation or a proliferation-inducing mutation dependent on telomere length of the cell. (A) In a cell with long telomeres and telomerase activity, a proliferation-promoting mutation will result in a strong proliferative advantage and can act as the tumor-initiating event. Cells with long telomeres arise from tissues that have a telomerase positive stem cell compartment such as the hematopoietic or intestinal system. In contrast, mutations in the TERT promoter do not provide a proliferative advantage, they are neutral and do not promote tumor formation. Cell states are depicted on the left; cells that acquire mutations are shown in red. A schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The dashed line indicates the critical telomere length at which cells are subjected to the Hayflick limit and stop proliferating or die. The red line indicates the telomere length changes predicted for cells that acquire either a proliferation-promoting mutation (top) or a TERT promoter mutation (bottom). The blue line indicates the telomere length changes predicted for wild-type cells. Indicated is a case where telomere shortening is suppressed by the TERT promoter mutations. However, since these cell already have long telomeres and/or naturally express telomerase, telomeres in neither wild-type cells or cells acquiring a proliferation inducing mutation will shorten to the point that the cells are subjected to the Hayflick limit. (B) Schematic as shown in (A) but for a telomerase negative cells with short telomeres. A proliferation-promoting mutation will also provide a growth advantage in telomerase-negative differentiated cells with short telomeres, however, these cells will enter replicative senescence or die. In contrast, a cell with short telomeres acquiring a TERT promoter mutation can bypass the Hayflick limit (dashed lines), immortalize, and outcompete its neighboring cells. Cell states are depicted on the left; cells that acquire mutations are shown in red. Schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The orange line indicates the telomere length changes predicted for wild-type cells. The table to the right shows the frequency of TERT promoter mutations found in different types of tumors (adapted form Heidenreich et al., 2014). The table includes references that report the specific tumor subtypes and frequencies used to generate this table.DOI:http://dx.doi.org/10.7554/eLife.07918.016
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fig6: Model explaining the tumor spectrum associated with TERT promoter mutations.Shown are the differential outcomes of a cell acquiring a cancer-associated TERT promoter mutation or a proliferation-inducing mutation dependent on telomere length of the cell. (A) In a cell with long telomeres and telomerase activity, a proliferation-promoting mutation will result in a strong proliferative advantage and can act as the tumor-initiating event. Cells with long telomeres arise from tissues that have a telomerase positive stem cell compartment such as the hematopoietic or intestinal system. In contrast, mutations in the TERT promoter do not provide a proliferative advantage, they are neutral and do not promote tumor formation. Cell states are depicted on the left; cells that acquire mutations are shown in red. A schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The dashed line indicates the critical telomere length at which cells are subjected to the Hayflick limit and stop proliferating or die. The red line indicates the telomere length changes predicted for cells that acquire either a proliferation-promoting mutation (top) or a TERT promoter mutation (bottom). The blue line indicates the telomere length changes predicted for wild-type cells. Indicated is a case where telomere shortening is suppressed by the TERT promoter mutations. However, since these cell already have long telomeres and/or naturally express telomerase, telomeres in neither wild-type cells or cells acquiring a proliferation inducing mutation will shorten to the point that the cells are subjected to the Hayflick limit. (B) Schematic as shown in (A) but for a telomerase negative cells with short telomeres. A proliferation-promoting mutation will also provide a growth advantage in telomerase-negative differentiated cells with short telomeres, however, these cells will enter replicative senescence or die. In contrast, a cell with short telomeres acquiring a TERT promoter mutation can bypass the Hayflick limit (dashed lines), immortalize, and outcompete its neighboring cells. Cell states are depicted on the left; cells that acquire mutations are shown in red. Schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The orange line indicates the telomere length changes predicted for wild-type cells. The table to the right shows the frequency of TERT promoter mutations found in different types of tumors (adapted form Heidenreich et al., 2014). The table includes references that report the specific tumor subtypes and frequencies used to generate this table.DOI:http://dx.doi.org/10.7554/eLife.07918.016

Mentions: Tumor-initiating events in these cancers predominantly drive proliferation pathways that spur formation of hyperplasia and niche-independent proliferation that allow incipient cancer cells to outcompete their neighbors (Barker et al., 2009; Zhou et al., 2009; Merlos-Suarez et al., 2011; Magee et al., 2012). In this setting, mutations in the TERT promoter or alterations in the telomerase biogenesis pathway might be at first neutral, not providing a direct proliferative advantage as telomeres are still long or telomerase is active (Figure 6A). During the genesis of these tumors, telomere shortening might present a challenge at a later stage when cells have already outcompeted their neighbors.10.7554/eLife.07918.016Figure 6.Model explaining the tumor spectrum associated with TERT promoter mutations.


Cancer-associated TERT promoter mutations abrogate telomerase silencing.

Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D - Elife (2015)

Model explaining the tumor spectrum associated with TERT promoter mutations.Shown are the differential outcomes of a cell acquiring a cancer-associated TERT promoter mutation or a proliferation-inducing mutation dependent on telomere length of the cell. (A) In a cell with long telomeres and telomerase activity, a proliferation-promoting mutation will result in a strong proliferative advantage and can act as the tumor-initiating event. Cells with long telomeres arise from tissues that have a telomerase positive stem cell compartment such as the hematopoietic or intestinal system. In contrast, mutations in the TERT promoter do not provide a proliferative advantage, they are neutral and do not promote tumor formation. Cell states are depicted on the left; cells that acquire mutations are shown in red. A schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The dashed line indicates the critical telomere length at which cells are subjected to the Hayflick limit and stop proliferating or die. The red line indicates the telomere length changes predicted for cells that acquire either a proliferation-promoting mutation (top) or a TERT promoter mutation (bottom). The blue line indicates the telomere length changes predicted for wild-type cells. Indicated is a case where telomere shortening is suppressed by the TERT promoter mutations. However, since these cell already have long telomeres and/or naturally express telomerase, telomeres in neither wild-type cells or cells acquiring a proliferation inducing mutation will shorten to the point that the cells are subjected to the Hayflick limit. (B) Schematic as shown in (A) but for a telomerase negative cells with short telomeres. A proliferation-promoting mutation will also provide a growth advantage in telomerase-negative differentiated cells with short telomeres, however, these cells will enter replicative senescence or die. In contrast, a cell with short telomeres acquiring a TERT promoter mutation can bypass the Hayflick limit (dashed lines), immortalize, and outcompete its neighboring cells. Cell states are depicted on the left; cells that acquire mutations are shown in red. Schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The orange line indicates the telomere length changes predicted for wild-type cells. The table to the right shows the frequency of TERT promoter mutations found in different types of tumors (adapted form Heidenreich et al., 2014). The table includes references that report the specific tumor subtypes and frequencies used to generate this table.DOI:http://dx.doi.org/10.7554/eLife.07918.016
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fig6: Model explaining the tumor spectrum associated with TERT promoter mutations.Shown are the differential outcomes of a cell acquiring a cancer-associated TERT promoter mutation or a proliferation-inducing mutation dependent on telomere length of the cell. (A) In a cell with long telomeres and telomerase activity, a proliferation-promoting mutation will result in a strong proliferative advantage and can act as the tumor-initiating event. Cells with long telomeres arise from tissues that have a telomerase positive stem cell compartment such as the hematopoietic or intestinal system. In contrast, mutations in the TERT promoter do not provide a proliferative advantage, they are neutral and do not promote tumor formation. Cell states are depicted on the left; cells that acquire mutations are shown in red. A schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The dashed line indicates the critical telomere length at which cells are subjected to the Hayflick limit and stop proliferating or die. The red line indicates the telomere length changes predicted for cells that acquire either a proliferation-promoting mutation (top) or a TERT promoter mutation (bottom). The blue line indicates the telomere length changes predicted for wild-type cells. Indicated is a case where telomere shortening is suppressed by the TERT promoter mutations. However, since these cell already have long telomeres and/or naturally express telomerase, telomeres in neither wild-type cells or cells acquiring a proliferation inducing mutation will shorten to the point that the cells are subjected to the Hayflick limit. (B) Schematic as shown in (A) but for a telomerase negative cells with short telomeres. A proliferation-promoting mutation will also provide a growth advantage in telomerase-negative differentiated cells with short telomeres, however, these cells will enter replicative senescence or die. In contrast, a cell with short telomeres acquiring a TERT promoter mutation can bypass the Hayflick limit (dashed lines), immortalize, and outcompete its neighboring cells. Cell states are depicted on the left; cells that acquire mutations are shown in red. Schematic depicting telomere length changes as a function of the number of cell divisions is shown on the right. The orange line indicates the telomere length changes predicted for wild-type cells. The table to the right shows the frequency of TERT promoter mutations found in different types of tumors (adapted form Heidenreich et al., 2014). The table includes references that report the specific tumor subtypes and frequencies used to generate this table.DOI:http://dx.doi.org/10.7554/eLife.07918.016
Mentions: Tumor-initiating events in these cancers predominantly drive proliferation pathways that spur formation of hyperplasia and niche-independent proliferation that allow incipient cancer cells to outcompete their neighbors (Barker et al., 2009; Zhou et al., 2009; Merlos-Suarez et al., 2011; Magee et al., 2012). In this setting, mutations in the TERT promoter or alterations in the telomerase biogenesis pathway might be at first neutral, not providing a direct proliferative advantage as telomeres are still long or telomerase is active (Figure 6A). During the genesis of these tumors, telomere shortening might present a challenge at a later stage when cells have already outcompeted their neighbors.10.7554/eLife.07918.016Figure 6.Model explaining the tumor spectrum associated with TERT promoter mutations.

Bottom Line: We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease.Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity.Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.

No MeSH data available.


Related in: MedlinePlus