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MECHANISM FOR GENETIC CHANGES IN THERAPY-INDUCED LEUKEMIA
Researchers at Fox Chase Cancer Center demonstrated how amplification and rearrangement of a gene associated with leukemia known as MLL is directly controlled by epigenetic factors, providing needed insights into a new therapeutic opportunity.
The findings indicate that these epigenetic regulators can be used as possible drug targets, paving the way for improved personalized, targeted medicines. The research by Johnathan Whetstine, Director of the Cancer Epigenetics Institute (CEI) at Fox Chase, is part of the storied history of pioneering research at Fox Chase on the connections between epigenetics, genetics, and cancer.
“His discovery establishes a new paradigm for understanding how chromosomal rearrangements occur,” said Alice Hungerford, a committed supporter of Fox Chase. She is also the widow of David Hungerford, a Fox Chase researcher and co-discoverer in 1959 of the Philadelphia chromosome, the first genetic defect linked to a specific type of cancer.
Peter Jones, a member of the CEI Advisory Board, agreed with Hungerford’s assessment of the study and added that it likely has implications beyond leukemia.
STUART BRIERS
For the study, Whetstine and his colleagues focused on the factors surrounding the recurrence of leukemia following chemotherapy, specifically how the MLL gene breaks apart, repairs, and amplifies.
Through multiple studies, Whetstine and colleagues showed for the first time that loss of a commonly deleted enzyme in leukemia, KDM3B, directly increases copies and rearrangement of MLL.
The team also demonstrated that when cells are given a specific type of chemotherapy drug called topoisomerase inhibitors, such as doxorubicin, protein levels of CTCF, a key transcription factor, and KDM3B are depleted by more than 50%. Based on those findings, they were able to prove that G9a, an inhibitor, could block the drug-induced change in MLL in human cells and mice.
Whetstine added that a well-developed drug against the G9a target could set the stage for further research into whether it suppresses the changes in humans moving forward.
STUDY DEMONSTRATES PROMISE OF NEW THERAPY FOR SEVERE FLU
In a study published in the prestigious journal Nature, researchers from Fox Chase Cancer Center have shown that a newly developed compound was able to block necroptosis, a type of cell death that leads to lung inflammation and damage, following infection with the influenza virus.
Necroptosis is triggered by the activation of the receptor interacting protein kinase 3 (RIPK3) pathway. This type of cell death produces strong immune responses by rupturing dead cells and releasing their contents throughout the body. When controlled, this form of cell death is effective at ridding the body of a virus. However, if unchecked, necroptosis can cause severe inflammation and lung damage and can even lead to death.
“We have now shown the possibility that RIPK3 can be inhibited, which is significant because it is central to programmed necrotic death in human tissues. Any disease involving chronic inflammation and necrotic death, such as colitis, lung fibrosis, liver disease, or psoriasis, could potentially benefit from blockade of this pathway,” said Siddharth Balachandran, lead author on the study and a Professor in the Cancer Signaling and Microenvironment Research Program.
“We found that by blocking necroptosis, you don’t get this form of explosive death and its resultant inflammation,” added Balachandran, who is also one of the Basic Science Co-Leaders of the Center for Immunology.
KOTRYNA ZUKAUSKAITE
“We found that by blocking necroptosis, you don’t get this form of explosive death and its resultant inflammation.”
He and his colleagues used mice infected with the flu virus to show that a newly developed RIPK3 inhibitor called UH15-38 selectively blocked necroptosis and dampened inflammation even when administered later in the course of an infection, a milestone in viral infection research. The new study comes on the heels of previous research in 2020 identifying a fundamental mechanism that detects the presence of the flu virus and rapidly destroys infected cells.
This mechanism could have implications for a variety of fields, including immunotherapy in the treatment of cancer, which is currently ineffective for 70% to 80% of patients. In these cases, the immune system does not recognize the cancer as foreign.
By mimicking an influenza virus infection in the cancer, the Balachandran lab hopes to activate necroptosis and rekindle responsiveness in patients whose cancers do not currently respond to immunotherapy.
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