ESTABLISHMENT OF A PRE-CLINICAL IN VIVO PLATFORM SPANNING LOW-RISK TO HIGH-RISK CLL
(Abstract release date: 05/19/16)
EHA Library. Knittel G. 06/10/16; 135150; S117
Mr. Gero Knittel
Contributions
Contributions
Abstract
Abstract: S117
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
CLL is the most common leukemia in the Western world. During CLL development, incipient CLL cells undergo a multistep mutational process, during which they acquire a set of genetic and/or epigenetic lesions, which ultimately result in the leukemic state. CLL-associated mutations can be classified into so-called driver mutations, which are essential for malignant growth and passenger mutations, which are functionally less significant. Recent work has revealed the identity of early, so-called trunk lesions and later-occurring subclonal mutations that are associated with disease progression and (chemo-)therapy resistance. Prominent examples for subclonal additional genetic events are ATM and TP53 mutations, which are both associated with resistance against genotoxic therapies.
Aims
We aimed at overcoming one of the biggest hurdles in preclinical CLL research - the lack of mouse models that faithfully mimic the genetic events leading to CLL development.
Methods
We combined the well established Eµ-TCL1 CLL mouse model with a floxed Tp53- or Atm-allele. We made use of the Cd19-Cre mouse to specifically delete Tp53 or Atm in the B cell compartment. The resulting Eµ-TCL1;Cd19Cre/wt;Tp53fl/fl (TCP) and Eµ-TCL1;Cd19Cre/wt;Atmfl/fl (TCA) mice were carefully characterized and subsequently used for treatment strategy testing.
Results
The increase of leukemic burden in the blood was significantly faster in TCP and TCA mice, when compared to the Eµ-TCL1;Cd19Cre/wt (TC) control. Thrombocytopenia and splenomegaly developed faster in the Atm- and Tp53-deficient models. In agreement with this faster disease progression, TCP and TCA mice succumbed faster to the disease than TC control animals (31.4 weeks, 36.9 weeks and 49.9 weeks, respectively).Despite faster diesase progression in TCP and TCA mice, splenomegaly at time of death was comparable in all three cohorts. Histologically, the three lines were indistinguishable.Richter's transformation, as defined by loss of Cd5 expression, a strong increase in cell size and a high proliferative index, was occassionally observed in TCP and TC mice, but not in the TCA cohort.Interestingly, TCA mice showed a significantly better response to cyclophosphamide when compared to TCP animals, but TC mice did not. Looking more closely at disease kinetics, we observed a significant increase in disease aggressiveness in the TC group up to the level of TCP mice, suggesting the selection of an aggressive clone under insufficient therapy.Lastly, we used the TCA model to investigate whether pharmacological inhibition of PARP, a treatment strategy proven to be effective in homologous recombination-deficient tumors of other entities, might be beneficial in ATM-deficient CLL as well. Indeed, we could show a strong and significant survival benefit by daily application of Parp inhibitor in our mice, an effect not observed in the Atm-proficient controls.
Conclusion
We have, based on the Eµ-TCL1 allele, generated mouse models mimicking the genetic alterations found in high-risk CLL patients, namely the loss of TP53 and ATM. These novel mouse models might be used as valuable tools for the development of new treatment strategies for these high risk groups. We have done so by assessing the effectiveness of Parp inhibition specifically in the Atm-deficient setting in this mouse model of CLL.
Session topic: CLL natural history and progression
Keyword(s): ATM, Mouse model, P53, Targeted therapy
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
CLL is the most common leukemia in the Western world. During CLL development, incipient CLL cells undergo a multistep mutational process, during which they acquire a set of genetic and/or epigenetic lesions, which ultimately result in the leukemic state. CLL-associated mutations can be classified into so-called driver mutations, which are essential for malignant growth and passenger mutations, which are functionally less significant. Recent work has revealed the identity of early, so-called trunk lesions and later-occurring subclonal mutations that are associated with disease progression and (chemo-)therapy resistance. Prominent examples for subclonal additional genetic events are ATM and TP53 mutations, which are both associated with resistance against genotoxic therapies.
Aims
We aimed at overcoming one of the biggest hurdles in preclinical CLL research - the lack of mouse models that faithfully mimic the genetic events leading to CLL development.
Methods
We combined the well established Eµ-TCL1 CLL mouse model with a floxed Tp53- or Atm-allele. We made use of the Cd19-Cre mouse to specifically delete Tp53 or Atm in the B cell compartment. The resulting Eµ-TCL1;Cd19Cre/wt;Tp53fl/fl (TCP) and Eµ-TCL1;Cd19Cre/wt;Atmfl/fl (TCA) mice were carefully characterized and subsequently used for treatment strategy testing.
Results
The increase of leukemic burden in the blood was significantly faster in TCP and TCA mice, when compared to the Eµ-TCL1;Cd19Cre/wt (TC) control. Thrombocytopenia and splenomegaly developed faster in the Atm- and Tp53-deficient models. In agreement with this faster disease progression, TCP and TCA mice succumbed faster to the disease than TC control animals (31.4 weeks, 36.9 weeks and 49.9 weeks, respectively).Despite faster diesase progression in TCP and TCA mice, splenomegaly at time of death was comparable in all three cohorts. Histologically, the three lines were indistinguishable.Richter's transformation, as defined by loss of Cd5 expression, a strong increase in cell size and a high proliferative index, was occassionally observed in TCP and TC mice, but not in the TCA cohort.Interestingly, TCA mice showed a significantly better response to cyclophosphamide when compared to TCP animals, but TC mice did not. Looking more closely at disease kinetics, we observed a significant increase in disease aggressiveness in the TC group up to the level of TCP mice, suggesting the selection of an aggressive clone under insufficient therapy.Lastly, we used the TCA model to investigate whether pharmacological inhibition of PARP, a treatment strategy proven to be effective in homologous recombination-deficient tumors of other entities, might be beneficial in ATM-deficient CLL as well. Indeed, we could show a strong and significant survival benefit by daily application of Parp inhibitor in our mice, an effect not observed in the Atm-proficient controls.
Conclusion
We have, based on the Eµ-TCL1 allele, generated mouse models mimicking the genetic alterations found in high-risk CLL patients, namely the loss of TP53 and ATM. These novel mouse models might be used as valuable tools for the development of new treatment strategies for these high risk groups. We have done so by assessing the effectiveness of Parp inhibition specifically in the Atm-deficient setting in this mouse model of CLL.
Session topic: CLL natural history and progression
Keyword(s): ATM, Mouse model, P53, Targeted therapy
Abstract: S117
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
CLL is the most common leukemia in the Western world. During CLL development, incipient CLL cells undergo a multistep mutational process, during which they acquire a set of genetic and/or epigenetic lesions, which ultimately result in the leukemic state. CLL-associated mutations can be classified into so-called driver mutations, which are essential for malignant growth and passenger mutations, which are functionally less significant. Recent work has revealed the identity of early, so-called trunk lesions and later-occurring subclonal mutations that are associated with disease progression and (chemo-)therapy resistance. Prominent examples for subclonal additional genetic events are ATM and TP53 mutations, which are both associated with resistance against genotoxic therapies.
Aims
We aimed at overcoming one of the biggest hurdles in preclinical CLL research - the lack of mouse models that faithfully mimic the genetic events leading to CLL development.
Methods
We combined the well established Eµ-TCL1 CLL mouse model with a floxed Tp53- or Atm-allele. We made use of the Cd19-Cre mouse to specifically delete Tp53 or Atm in the B cell compartment. The resulting Eµ-TCL1;Cd19Cre/wt;Tp53fl/fl (TCP) and Eµ-TCL1;Cd19Cre/wt;Atmfl/fl (TCA) mice were carefully characterized and subsequently used for treatment strategy testing.
Results
The increase of leukemic burden in the blood was significantly faster in TCP and TCA mice, when compared to the Eµ-TCL1;Cd19Cre/wt (TC) control. Thrombocytopenia and splenomegaly developed faster in the Atm- and Tp53-deficient models. In agreement with this faster disease progression, TCP and TCA mice succumbed faster to the disease than TC control animals (31.4 weeks, 36.9 weeks and 49.9 weeks, respectively).Despite faster diesase progression in TCP and TCA mice, splenomegaly at time of death was comparable in all three cohorts. Histologically, the three lines were indistinguishable.Richter's transformation, as defined by loss of Cd5 expression, a strong increase in cell size and a high proliferative index, was occassionally observed in TCP and TC mice, but not in the TCA cohort.Interestingly, TCA mice showed a significantly better response to cyclophosphamide when compared to TCP animals, but TC mice did not. Looking more closely at disease kinetics, we observed a significant increase in disease aggressiveness in the TC group up to the level of TCP mice, suggesting the selection of an aggressive clone under insufficient therapy.Lastly, we used the TCA model to investigate whether pharmacological inhibition of PARP, a treatment strategy proven to be effective in homologous recombination-deficient tumors of other entities, might be beneficial in ATM-deficient CLL as well. Indeed, we could show a strong and significant survival benefit by daily application of Parp inhibitor in our mice, an effect not observed in the Atm-proficient controls.
Conclusion
We have, based on the Eµ-TCL1 allele, generated mouse models mimicking the genetic alterations found in high-risk CLL patients, namely the loss of TP53 and ATM. These novel mouse models might be used as valuable tools for the development of new treatment strategies for these high risk groups. We have done so by assessing the effectiveness of Parp inhibition specifically in the Atm-deficient setting in this mouse model of CLL.
Session topic: CLL natural history and progression
Keyword(s): ATM, Mouse model, P53, Targeted therapy
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
CLL is the most common leukemia in the Western world. During CLL development, incipient CLL cells undergo a multistep mutational process, during which they acquire a set of genetic and/or epigenetic lesions, which ultimately result in the leukemic state. CLL-associated mutations can be classified into so-called driver mutations, which are essential for malignant growth and passenger mutations, which are functionally less significant. Recent work has revealed the identity of early, so-called trunk lesions and later-occurring subclonal mutations that are associated with disease progression and (chemo-)therapy resistance. Prominent examples for subclonal additional genetic events are ATM and TP53 mutations, which are both associated with resistance against genotoxic therapies.
Aims
We aimed at overcoming one of the biggest hurdles in preclinical CLL research - the lack of mouse models that faithfully mimic the genetic events leading to CLL development.
Methods
We combined the well established Eµ-TCL1 CLL mouse model with a floxed Tp53- or Atm-allele. We made use of the Cd19-Cre mouse to specifically delete Tp53 or Atm in the B cell compartment. The resulting Eµ-TCL1;Cd19Cre/wt;Tp53fl/fl (TCP) and Eµ-TCL1;Cd19Cre/wt;Atmfl/fl (TCA) mice were carefully characterized and subsequently used for treatment strategy testing.
Results
The increase of leukemic burden in the blood was significantly faster in TCP and TCA mice, when compared to the Eµ-TCL1;Cd19Cre/wt (TC) control. Thrombocytopenia and splenomegaly developed faster in the Atm- and Tp53-deficient models. In agreement with this faster disease progression, TCP and TCA mice succumbed faster to the disease than TC control animals (31.4 weeks, 36.9 weeks and 49.9 weeks, respectively).Despite faster diesase progression in TCP and TCA mice, splenomegaly at time of death was comparable in all three cohorts. Histologically, the three lines were indistinguishable.Richter's transformation, as defined by loss of Cd5 expression, a strong increase in cell size and a high proliferative index, was occassionally observed in TCP and TC mice, but not in the TCA cohort.Interestingly, TCA mice showed a significantly better response to cyclophosphamide when compared to TCP animals, but TC mice did not. Looking more closely at disease kinetics, we observed a significant increase in disease aggressiveness in the TC group up to the level of TCP mice, suggesting the selection of an aggressive clone under insufficient therapy.Lastly, we used the TCA model to investigate whether pharmacological inhibition of PARP, a treatment strategy proven to be effective in homologous recombination-deficient tumors of other entities, might be beneficial in ATM-deficient CLL as well. Indeed, we could show a strong and significant survival benefit by daily application of Parp inhibitor in our mice, an effect not observed in the Atm-proficient controls.
Conclusion
We have, based on the Eµ-TCL1 allele, generated mouse models mimicking the genetic alterations found in high-risk CLL patients, namely the loss of TP53 and ATM. These novel mouse models might be used as valuable tools for the development of new treatment strategies for these high risk groups. We have done so by assessing the effectiveness of Parp inhibition specifically in the Atm-deficient setting in this mouse model of CLL.
Session topic: CLL natural history and progression
Keyword(s): ATM, Mouse model, P53, Targeted therapy
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