Contributions
Abstract: PB1654
Type: Publication Only
Background
Leukemia stem cells (LSCs) are considered as the main reason for treatment failure and relapse in acute myeloid leukemia. Overexpression of Bcl-2 anti-apoptotic proteins is associated with the survival and self-renewal of LSCs
Aims
To observe the effect for AT101 to eliminate AML stem cells and its underlying mechanism.
Methods
Use CD34+CD38-CD123+ KG1α and primary AML CD34+ cells as research object.
Results
In this study, we demonstrated that AT101, a BH3 mimetic pan-Bcl-2 inhibitor, was significantly and effectively cytotoxic towards CD34+CD38-CD123+ KG1α and primary AML CD34+ cells, with slight effect on CD34+ normal hematopoietic cells. And the mechanism was closely associated with activation of intrinsic apoptotic pathway, such as loss of mitochondrial membrane potential and caspase activation, along with disturbance of DNA damage response. Further analysis on AML patients’ clinical characteristics revealed that the ex vivo efficacy of AT101 in primary samples was significantly correlated to hyperleukocytosis or FLT3-ITD mutation. Besides, AT101 exhibited exciting effect on CD34+ blasts from patients who are old or cannot achieve CR after induction therapy.
Conclusion
In conclusion, Together, these findings provides potentiality for the use of AT101 to treat relapse and refractory AML as alternative salvage regime in the future, including those clinically characterized by one or more adverse prognostic abnormalities.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemic Stem Cell, DNA Damage, BCL2, AML
Abstract: PB1654
Type: Publication Only
Background
Leukemia stem cells (LSCs) are considered as the main reason for treatment failure and relapse in acute myeloid leukemia. Overexpression of Bcl-2 anti-apoptotic proteins is associated with the survival and self-renewal of LSCs
Aims
To observe the effect for AT101 to eliminate AML stem cells and its underlying mechanism.
Methods
Use CD34+CD38-CD123+ KG1α and primary AML CD34+ cells as research object.
Results
In this study, we demonstrated that AT101, a BH3 mimetic pan-Bcl-2 inhibitor, was significantly and effectively cytotoxic towards CD34+CD38-CD123+ KG1α and primary AML CD34+ cells, with slight effect on CD34+ normal hematopoietic cells. And the mechanism was closely associated with activation of intrinsic apoptotic pathway, such as loss of mitochondrial membrane potential and caspase activation, along with disturbance of DNA damage response. Further analysis on AML patients’ clinical characteristics revealed that the ex vivo efficacy of AT101 in primary samples was significantly correlated to hyperleukocytosis or FLT3-ITD mutation. Besides, AT101 exhibited exciting effect on CD34+ blasts from patients who are old or cannot achieve CR after induction therapy.
Conclusion
In conclusion, Together, these findings provides potentiality for the use of AT101 to treat relapse and refractory AML as alternative salvage regime in the future, including those clinically characterized by one or more adverse prognostic abnormalities.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemic Stem Cell, DNA Damage, BCL2, AML