LOSS OF FUNCTION SETD2 MUTATIONS LEAD TO RESISTANCE TO DNA DAMAGING CHEMOTHERAPY IN LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Kahn J. 06/11/16; 135217; S461
Ms. Josephine Kahn
Contributions
Contributions
Abstract
Abstract: S461
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C13
Background
Relapsed leukemia has a poor survival, which can be attributed to the relative chemotherapy resistance of this disease entity. While the consequences of chemotherapy resistance are clear, the genetic alterations underlying resistance remain poorly understood. We recently identified somatic mutations that are specifically enriched in relapsed leukemia, including a novel loss of function mutation in the epigenetic regulator SETD2. SETD2 is the only known mammalian Histone 3 Lysine (H3K36) trimethyltransferase and its role in DNA mismatch repair was recently established. In view of the presence of SETD2 mutations in relapsed leukemia, and the role of SETD2 in DNA repair, we hypothesized that SETD2 plays a role in chemotherapy resistance in relapsed leukemia.
Aims
To investigate the role of SETD2 loss of function mutations in chemotherapy resistance and identify therapeutic targets for SETD2 mutant leukemia.
Methods
We employed two different models to study the role of SETD2 in chemotherapy resistance, which include an isogenic human leukemia model engineered with CRISPR-Cas9 and a murine leukemia with Setd2 conditional knockout and retroviral expression of MLL-AF9. We studied the presence and mechanism of chemotherapy resistance in both models.
Results
We demonstrate that loss of function SETD2 mutations cause resistance to chemotherapy. The resistance is specific to DNA damaging chemotherapies, including the commonly used agents 6-thioguanine and cytarabine. In contrast, no resistance to the non-DNA damaging agent L-asparaginase was observed. In addition to causing an increase in IC50 values, loss of SETD2 results in a strong competitive advantage in the presence of DNA damaging agents, mimicking the selective pressure of SETD2 mutant clones during treatment in patients (Fig. 1). We further establish that the resistance is caused by an abrogated DNA damage response as demonstrated by a decreased phosphorylation of CHK1 and CHK2 and a reduced apoptotic response after treatment with DNA damaging therapies. In our conditional knockout model, we show that, in addition to causing a significant acceleration of leukemia, SETD2 loss causes resistance to cytarabine and doxorubicin treatment in vivo. Finally, we show that WEE1 inhibition specifically targets SETD2 mutant cells and re-sensitizes to chemotherapy, hereby providing a treatment option for SETD2 mutant, chemotherapy resistant leukemia.
Conclusion
While relapsed leukemia is known to be chemotherapy resistant, the mechanisms of resistance remain poorly understood. This study is the first to show that loss of function SETD2 mutations confer chemotherapy resistance in leukemia. In addition, we show that treatment with a WEE1 inhibitor – which is currently in clinical trials - is able to specifically target SETD2 mutant leukemia and reverse chemotherapy resistance. Hence, this study supports a prominent role for loss of function SETD2 mutations in disease progression and chemotherapy resistance in leukemia, as well as providing evidence for a potential therapy to treat SETD2 mutant, chemotherapy resistant leukemia.
Session topic: AML Biology Mutant FLT
Keyword(s): Chemotherapy, Epigenetic, Leukemia, Resistance
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C13
Background
Relapsed leukemia has a poor survival, which can be attributed to the relative chemotherapy resistance of this disease entity. While the consequences of chemotherapy resistance are clear, the genetic alterations underlying resistance remain poorly understood. We recently identified somatic mutations that are specifically enriched in relapsed leukemia, including a novel loss of function mutation in the epigenetic regulator SETD2. SETD2 is the only known mammalian Histone 3 Lysine (H3K36) trimethyltransferase and its role in DNA mismatch repair was recently established. In view of the presence of SETD2 mutations in relapsed leukemia, and the role of SETD2 in DNA repair, we hypothesized that SETD2 plays a role in chemotherapy resistance in relapsed leukemia.
Aims
To investigate the role of SETD2 loss of function mutations in chemotherapy resistance and identify therapeutic targets for SETD2 mutant leukemia.
Methods
We employed two different models to study the role of SETD2 in chemotherapy resistance, which include an isogenic human leukemia model engineered with CRISPR-Cas9 and a murine leukemia with Setd2 conditional knockout and retroviral expression of MLL-AF9. We studied the presence and mechanism of chemotherapy resistance in both models.
Results
We demonstrate that loss of function SETD2 mutations cause resistance to chemotherapy. The resistance is specific to DNA damaging chemotherapies, including the commonly used agents 6-thioguanine and cytarabine. In contrast, no resistance to the non-DNA damaging agent L-asparaginase was observed. In addition to causing an increase in IC50 values, loss of SETD2 results in a strong competitive advantage in the presence of DNA damaging agents, mimicking the selective pressure of SETD2 mutant clones during treatment in patients (Fig. 1). We further establish that the resistance is caused by an abrogated DNA damage response as demonstrated by a decreased phosphorylation of CHK1 and CHK2 and a reduced apoptotic response after treatment with DNA damaging therapies. In our conditional knockout model, we show that, in addition to causing a significant acceleration of leukemia, SETD2 loss causes resistance to cytarabine and doxorubicin treatment in vivo. Finally, we show that WEE1 inhibition specifically targets SETD2 mutant cells and re-sensitizes to chemotherapy, hereby providing a treatment option for SETD2 mutant, chemotherapy resistant leukemia.
Conclusion
While relapsed leukemia is known to be chemotherapy resistant, the mechanisms of resistance remain poorly understood. This study is the first to show that loss of function SETD2 mutations confer chemotherapy resistance in leukemia. In addition, we show that treatment with a WEE1 inhibitor – which is currently in clinical trials - is able to specifically target SETD2 mutant leukemia and reverse chemotherapy resistance. Hence, this study supports a prominent role for loss of function SETD2 mutations in disease progression and chemotherapy resistance in leukemia, as well as providing evidence for a potential therapy to treat SETD2 mutant, chemotherapy resistant leukemia.
Session topic: AML Biology Mutant FLT
Keyword(s): Chemotherapy, Epigenetic, Leukemia, Resistance
Abstract: S461
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C13
Background
Relapsed leukemia has a poor survival, which can be attributed to the relative chemotherapy resistance of this disease entity. While the consequences of chemotherapy resistance are clear, the genetic alterations underlying resistance remain poorly understood. We recently identified somatic mutations that are specifically enriched in relapsed leukemia, including a novel loss of function mutation in the epigenetic regulator SETD2. SETD2 is the only known mammalian Histone 3 Lysine (H3K36) trimethyltransferase and its role in DNA mismatch repair was recently established. In view of the presence of SETD2 mutations in relapsed leukemia, and the role of SETD2 in DNA repair, we hypothesized that SETD2 plays a role in chemotherapy resistance in relapsed leukemia.
Aims
To investigate the role of SETD2 loss of function mutations in chemotherapy resistance and identify therapeutic targets for SETD2 mutant leukemia.
Methods
We employed two different models to study the role of SETD2 in chemotherapy resistance, which include an isogenic human leukemia model engineered with CRISPR-Cas9 and a murine leukemia with Setd2 conditional knockout and retroviral expression of MLL-AF9. We studied the presence and mechanism of chemotherapy resistance in both models.
Results
We demonstrate that loss of function SETD2 mutations cause resistance to chemotherapy. The resistance is specific to DNA damaging chemotherapies, including the commonly used agents 6-thioguanine and cytarabine. In contrast, no resistance to the non-DNA damaging agent L-asparaginase was observed. In addition to causing an increase in IC50 values, loss of SETD2 results in a strong competitive advantage in the presence of DNA damaging agents, mimicking the selective pressure of SETD2 mutant clones during treatment in patients (Fig. 1). We further establish that the resistance is caused by an abrogated DNA damage response as demonstrated by a decreased phosphorylation of CHK1 and CHK2 and a reduced apoptotic response after treatment with DNA damaging therapies. In our conditional knockout model, we show that, in addition to causing a significant acceleration of leukemia, SETD2 loss causes resistance to cytarabine and doxorubicin treatment in vivo. Finally, we show that WEE1 inhibition specifically targets SETD2 mutant cells and re-sensitizes to chemotherapy, hereby providing a treatment option for SETD2 mutant, chemotherapy resistant leukemia.
Conclusion
While relapsed leukemia is known to be chemotherapy resistant, the mechanisms of resistance remain poorly understood. This study is the first to show that loss of function SETD2 mutations confer chemotherapy resistance in leukemia. In addition, we show that treatment with a WEE1 inhibitor – which is currently in clinical trials - is able to specifically target SETD2 mutant leukemia and reverse chemotherapy resistance. Hence, this study supports a prominent role for loss of function SETD2 mutations in disease progression and chemotherapy resistance in leukemia, as well as providing evidence for a potential therapy to treat SETD2 mutant, chemotherapy resistant leukemia.
Session topic: AML Biology Mutant FLT
Keyword(s): Chemotherapy, Epigenetic, Leukemia, Resistance
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C13
Background
Relapsed leukemia has a poor survival, which can be attributed to the relative chemotherapy resistance of this disease entity. While the consequences of chemotherapy resistance are clear, the genetic alterations underlying resistance remain poorly understood. We recently identified somatic mutations that are specifically enriched in relapsed leukemia, including a novel loss of function mutation in the epigenetic regulator SETD2. SETD2 is the only known mammalian Histone 3 Lysine (H3K36) trimethyltransferase and its role in DNA mismatch repair was recently established. In view of the presence of SETD2 mutations in relapsed leukemia, and the role of SETD2 in DNA repair, we hypothesized that SETD2 plays a role in chemotherapy resistance in relapsed leukemia.
Aims
To investigate the role of SETD2 loss of function mutations in chemotherapy resistance and identify therapeutic targets for SETD2 mutant leukemia.
Methods
We employed two different models to study the role of SETD2 in chemotherapy resistance, which include an isogenic human leukemia model engineered with CRISPR-Cas9 and a murine leukemia with Setd2 conditional knockout and retroviral expression of MLL-AF9. We studied the presence and mechanism of chemotherapy resistance in both models.
Results
We demonstrate that loss of function SETD2 mutations cause resistance to chemotherapy. The resistance is specific to DNA damaging chemotherapies, including the commonly used agents 6-thioguanine and cytarabine. In contrast, no resistance to the non-DNA damaging agent L-asparaginase was observed. In addition to causing an increase in IC50 values, loss of SETD2 results in a strong competitive advantage in the presence of DNA damaging agents, mimicking the selective pressure of SETD2 mutant clones during treatment in patients (Fig. 1). We further establish that the resistance is caused by an abrogated DNA damage response as demonstrated by a decreased phosphorylation of CHK1 and CHK2 and a reduced apoptotic response after treatment with DNA damaging therapies. In our conditional knockout model, we show that, in addition to causing a significant acceleration of leukemia, SETD2 loss causes resistance to cytarabine and doxorubicin treatment in vivo. Finally, we show that WEE1 inhibition specifically targets SETD2 mutant cells and re-sensitizes to chemotherapy, hereby providing a treatment option for SETD2 mutant, chemotherapy resistant leukemia.
Conclusion
While relapsed leukemia is known to be chemotherapy resistant, the mechanisms of resistance remain poorly understood. This study is the first to show that loss of function SETD2 mutations confer chemotherapy resistance in leukemia. In addition, we show that treatment with a WEE1 inhibitor – which is currently in clinical trials - is able to specifically target SETD2 mutant leukemia and reverse chemotherapy resistance. Hence, this study supports a prominent role for loss of function SETD2 mutations in disease progression and chemotherapy resistance in leukemia, as well as providing evidence for a potential therapy to treat SETD2 mutant, chemotherapy resistant leukemia.
Session topic: AML Biology Mutant FLT
Keyword(s): Chemotherapy, Epigenetic, Leukemia, Resistance
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