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Researchers have identified a promising therapeutic target for t(8;21) acute myeloid leukemia (AML), according to preclinical data published in Cancer Cell.
The fusion protein RUNX1/ETO drives t(8;21) AML by promoting cell-cycle progression.
Using an RNAi screen, the team recognized the cell-cycle regulator cyclin D2 (CCND2) as having critical involvement in RUNX1/ETO-driven leukemia propagation.
And when they knocked down CCND2 with palbociclib, a drug already approved for breast cancer, leukemic expansion of human AML cells and engraftment in murine models were significantly impaired.
"Our discovery that this treatment can be effective in AML is an important step towards a more effective and less toxic treatment for patients with this form of leukemia,” said study author Olaf Heidenreich, PhD, from the Wolfson Childhood Cancer Research Centre at Newcastle University in the U.K.
After identifying the fusion protein with the RNAi screen, the investigators determined that RUNX1/ETO regulates CCND2 transcription. They knocked down the fusion protein and found the expression of CCND2 was diminished in primary AML blasts. They therefore concluded that RUNX1/ETO maintains CCND2 expression.
The team then examined the significance of CCND2 in engraftment, proliferation, and clonal expansion of AML cells and its impact on the accumulation of cells in the G1 phase of the cell cycle. They found that depletion of CCND2 inhibited cell proliferation and clonogenic capacity and arrested the cell cycle in G0/G1 without increasing apoptosis.
They also confirmed that knockdown of RUNX1/ETO or CCND2 did not affect the expression of other D cyclins and G1 cyclin-dependent kinase (CDK)-CCND complexes, such as CDK4/6.
Next, they explored whether RUNX1/ETO-expressing cells were sensitive to the CDK4/6 inhibitor palbociclib. AML cells were highly sensitive to palbociclib and did not proliferate during drug exposure.
The researchers cultured cells from t(8;21)-positive and -negative AML patients and found palbociclib to cause a dose-dependent inhibition of proliferation of AML blasts.
They also tested palbociclib on a sample from a relapsed t(8;21) AML patient. The sample was highly sensitive to palbociclib, with a five-fold reduction in cell numbers using 300 nM of drug.
The investigators conducted in vivo experiments with palbociclib in mice transplanted with AML cells. Mice treated with palbociclib at doses of 100–150 mg/kg had a significantly longer survival than control mice.
Finally, the team examined whether interference with G1 CDK activity would create other vulnerabilities, such as activating KIT mutations, which are frequent secondary mutations found in t(8;21) AML.
They found that G1 CDK inhibition sensitized AML cells toward KIT inhibition, suggesting that “concurrent targeting of the two mutations may offer substantial therapeutic benefit.”
The team plans to conduct experiments that will refine the precise palbociclib dose in AML either as a single agent or in combination.
This study was supported by grants from Bloodwise, Children with Cancer, North of England Children’s Cancer Research Fund, Children's Cancer and Leukaemia Group, and a CRUK program grant in addition to an Aga Khan PhD studentship, a University Sains Malaysia PhD studentship, and an NC3R fellowship.
The authors had no competing interests to disclose.
Researchers have identified a promising therapeutic target for t(8;21) acute myeloid leukemia (AML), according to preclinical data published in Cancer Cell.
The fusion protein RUNX1/ETO drives t(8;21) AML by promoting cell-cycle progression.
Using an RNAi screen, the team recognized the cell-cycle regulator cyclin D2 (CCND2) as having critical involvement in RUNX1/ETO-driven leukemia propagation.
And when they knocked down CCND2 with palbociclib, a drug already approved for breast cancer, leukemic expansion of human AML cells and engraftment in murine models were significantly impaired.
"Our discovery that this treatment can be effective in AML is an important step towards a more effective and less toxic treatment for patients with this form of leukemia,” said study author Olaf Heidenreich, PhD, from the Wolfson Childhood Cancer Research Centre at Newcastle University in the U.K.
After identifying the fusion protein with the RNAi screen, the investigators determined that RUNX1/ETO regulates CCND2 transcription. They knocked down the fusion protein and found the expression of CCND2 was diminished in primary AML blasts. They therefore concluded that RUNX1/ETO maintains CCND2 expression.
The team then examined the significance of CCND2 in engraftment, proliferation, and clonal expansion of AML cells and its impact on the accumulation of cells in the G1 phase of the cell cycle. They found that depletion of CCND2 inhibited cell proliferation and clonogenic capacity and arrested the cell cycle in G0/G1 without increasing apoptosis.
They also confirmed that knockdown of RUNX1/ETO or CCND2 did not affect the expression of other D cyclins and G1 cyclin-dependent kinase (CDK)-CCND complexes, such as CDK4/6.
Next, they explored whether RUNX1/ETO-expressing cells were sensitive to the CDK4/6 inhibitor palbociclib. AML cells were highly sensitive to palbociclib and did not proliferate during drug exposure.
The researchers cultured cells from t(8;21)-positive and -negative AML patients and found palbociclib to cause a dose-dependent inhibition of proliferation of AML blasts.
They also tested palbociclib on a sample from a relapsed t(8;21) AML patient. The sample was highly sensitive to palbociclib, with a five-fold reduction in cell numbers using 300 nM of drug.
The investigators conducted in vivo experiments with palbociclib in mice transplanted with AML cells. Mice treated with palbociclib at doses of 100–150 mg/kg had a significantly longer survival than control mice.
Finally, the team examined whether interference with G1 CDK activity would create other vulnerabilities, such as activating KIT mutations, which are frequent secondary mutations found in t(8;21) AML.
They found that G1 CDK inhibition sensitized AML cells toward KIT inhibition, suggesting that “concurrent targeting of the two mutations may offer substantial therapeutic benefit.”
The team plans to conduct experiments that will refine the precise palbociclib dose in AML either as a single agent or in combination.
This study was supported by grants from Bloodwise, Children with Cancer, North of England Children’s Cancer Research Fund, Children's Cancer and Leukaemia Group, and a CRUK program grant in addition to an Aga Khan PhD studentship, a University Sains Malaysia PhD studentship, and an NC3R fellowship.
The authors had no competing interests to disclose.
Researchers have identified a promising therapeutic target for t(8;21) acute myeloid leukemia (AML), according to preclinical data published in Cancer Cell.
The fusion protein RUNX1/ETO drives t(8;21) AML by promoting cell-cycle progression.
Using an RNAi screen, the team recognized the cell-cycle regulator cyclin D2 (CCND2) as having critical involvement in RUNX1/ETO-driven leukemia propagation.
And when they knocked down CCND2 with palbociclib, a drug already approved for breast cancer, leukemic expansion of human AML cells and engraftment in murine models were significantly impaired.
"Our discovery that this treatment can be effective in AML is an important step towards a more effective and less toxic treatment for patients with this form of leukemia,” said study author Olaf Heidenreich, PhD, from the Wolfson Childhood Cancer Research Centre at Newcastle University in the U.K.
After identifying the fusion protein with the RNAi screen, the investigators determined that RUNX1/ETO regulates CCND2 transcription. They knocked down the fusion protein and found the expression of CCND2 was diminished in primary AML blasts. They therefore concluded that RUNX1/ETO maintains CCND2 expression.
The team then examined the significance of CCND2 in engraftment, proliferation, and clonal expansion of AML cells and its impact on the accumulation of cells in the G1 phase of the cell cycle. They found that depletion of CCND2 inhibited cell proliferation and clonogenic capacity and arrested the cell cycle in G0/G1 without increasing apoptosis.
They also confirmed that knockdown of RUNX1/ETO or CCND2 did not affect the expression of other D cyclins and G1 cyclin-dependent kinase (CDK)-CCND complexes, such as CDK4/6.
Next, they explored whether RUNX1/ETO-expressing cells were sensitive to the CDK4/6 inhibitor palbociclib. AML cells were highly sensitive to palbociclib and did not proliferate during drug exposure.
The researchers cultured cells from t(8;21)-positive and -negative AML patients and found palbociclib to cause a dose-dependent inhibition of proliferation of AML blasts.
They also tested palbociclib on a sample from a relapsed t(8;21) AML patient. The sample was highly sensitive to palbociclib, with a five-fold reduction in cell numbers using 300 nM of drug.
The investigators conducted in vivo experiments with palbociclib in mice transplanted with AML cells. Mice treated with palbociclib at doses of 100–150 mg/kg had a significantly longer survival than control mice.
Finally, the team examined whether interference with G1 CDK activity would create other vulnerabilities, such as activating KIT mutations, which are frequent secondary mutations found in t(8;21) AML.
They found that G1 CDK inhibition sensitized AML cells toward KIT inhibition, suggesting that “concurrent targeting of the two mutations may offer substantial therapeutic benefit.”
The team plans to conduct experiments that will refine the precise palbociclib dose in AML either as a single agent or in combination.
This study was supported by grants from Bloodwise, Children with Cancer, North of England Children’s Cancer Research Fund, Children's Cancer and Leukaemia Group, and a CRUK program grant in addition to an Aga Khan PhD studentship, a University Sains Malaysia PhD studentship, and an NC3R fellowship.
The authors had no competing interests to disclose.