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Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.
Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.
Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.