Scientists discover how leukemia cells evade treatment

Rutgers University

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Researchers from Rutgers Health and other institutions have discovered why a powerful leukemia drug eventually fails in most patients – and found a potential way to overcome that resistance.

Team members identified a protein that lets cancer cells reshape their energy-producing mitochondria in ways that protect them from venetoclax (brand name, Venclexta), a standard treatment for acute myeloid leukemia that often loses effectiveness after prolonged use.

Blocking that protein with experimental compounds in mice with human acute myeloid leukemia restored the drug's effectiveness and prolonged survival.

The findings, published in Science Advances, reveal an unexpected mechanism of drug resistance and suggest a new approach for one of the deadliest blood cancers in adults.

"We found that mitochondria change their shape to prevent apoptosis, a type of cell suicide induced by these drugs," said senior study author Christina Glytsou, an assistant professor at Rutgers' Ernest Mario School of Pharmacy and Robert Wood Johnson Medical School and a member of the Rutgers Cancer Institute’s Pediatric Hematology and Oncology Research Center of Excellence (NJPHORCE).

Although venetoclax induces remission in many acute myeloid leukemia patients by triggering cancer cell death, resistance develops in nearly all cases. The five-year survival rate remains at 30% and the disease kills about 11,000 Americans each year.

Using electron microscopy and genetic screens, members of Glytsou's team discovered that treatment-resistant leukemia cells produce high levels of a protein called OPA1, which controls the internal structure of mitochondria. Cells with these elevated OPA1 levels develop tighter, more numerous folds in their mitochondrial membranes — compartments called cristae – that trap cytochrome c, a molecule that normally triggers cell death when released.

The researchers confirmed the finding by examining cells from leukemia patients. Those who had relapsed after treatment showed sharply narrower cristae than newly diagnosed patients, with the most pronounced changes in patients who had been treated with venetoclax.

To test whether they restore drug efficacy by blocking this structural change, team members used two experimental OPA1 inhibitors. In mice transplanted with human leukemia cells, combining the OPA1 inhibitors with venetoclax at least doubled survival time compared with venetoclax alone.

The combination worked across diverse leukemia subtypes, including cells with mutations in the p53 gene, which are strongly associated with treatment resistance and poor outcomes.

The OPA1 inhibitors also appear to work through additional mechanisms beyond restoring cell death pathways. The experiments revealed that cells lacking OPA1 become heavily dependent on the nutrient glutamine and vulnerable to ferroptosis, a different form of cell death driven by iron and lipid damage.

Tests in mice showed the compounds didn’t harm normal blood cell production, a critical safety consideration for any potential leukemia treatment in humans.

The research is in early stages. The OPA1 inhibitors, developed by collaborators at the University of Padua in Italy, are lead compounds that require further refinement before human testing can begin.

“There is still some time to go through,” Glytsou said, adding that a third generation of compounds may be needed to improve the drugs' solubility and other properties.

Still, the work offers a promising direction for treating resistant leukemia and potentially other cancers, said Glytsou, who is also a member of the cancer institute’s cancer pharmacology and cancer metabolism and immunology research programs. 

OPA1 is overexpressed in multiple cancer types and associated with poor prognosis and therapy resistance in breast cancer, lung cancer and other malignancies.

Rutgers Cancer Institute, together with RWJBarnabas Health, is New Jersey’s only National Cancer Institute-designated Comprehensive Cancer Center.

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Journal

Science Advances

DOI

10.1126/sciadv.adx8662 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia

Article Publication Date

15-Oct-2025

COI Statement

L.S. and A.P. disclose that they are inventors of a submitted patent application by the University of Padova and Veneto Institute of Molecular Medicine covering MYLS22 and its derivatives as Opa1 inhibitors (WIPO|PCT WO2021/008669). I.A. and C.G. disclose that they are inventors of a patent application by the New York University, “Methods and compositions for sensitizing leukemia cells to drug-induced apoptosis” (PCT/US20/30975). K.G. has pending intellectual property patent protection on TTLL4 as a target of chemical perturbation in AML. K.G. has received research funding from iOnctura, S.A., unrelated to this work. A.V. has received research funding from BMS, Jannsen, MedPacto, Curis, Prelude, Halia, and Ryvu Eli Lilly and Company. A.V. has received compensation as a scientific advisor to Stelexis Therapeutics, Calico, and Aurigene and has equity ownership in Roshon, Stelexis, and ClinStreet. All other authors declare that they have no competing interests.

 D.E.I. 

Native American stereotypes, as seen by Native Americans

Cornell University

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ITHACA, N.Y. — Asked to list stereotypes they had heard about themselves or other Native Americans, more than 200 middle school-age citizens of the Eastern Band of Cherokee Indians, a federally recognized nation located in rural North Carolina, most often cited cultural activities, financial privilege and substance abuse.

The Cornell-led study, among the first to explore Native Americans’ perceptions, rather than those of a white majority or other ethnic groups, showed the early adolescents gaining awareness of stereotypes as they moved from sixth through eighth grade, and how context influenced that awareness. Cherokee students attending a pair of more diverse public schools in which they were a minority identified more stereotypes than counterparts at a tribal school.

Understanding prevalent stereotypes – whether they are positive or negative, believed or not – could help schools and parents counter them to support students’ development, said Adam Hoffman, assistant professor in the Department of Psychology and College of Human Ecology.

“Research has shown that stereotypes, even positive ones, are detrimental and can impact teens’ academic motivation and achievement, mental health and well-being,” Hoffman said. “Knowing what kinds of things these kids are hearing and thinking about themselves and Native Americans is important to start working on dismantling those stereotypes.”

Hoffman is the first author of “Early Adolescent Cherokees’ Reports of Stereotypes About Native Americans,” published Sept. 25 in the journal Youth & Society. Co-authors are Beth Kurtz-Costes, professor at the University of North Carolina, Chapel Hill; Ash Moomaw, doctoral student at Ball State University; and Bette Fitzgerald and Angela Gunter, teachers at two of the middle schools from which the youth were recruited to be part of the study.

Research to date on Native American stereotypes has primarily featured samples of white adults, using quantitative assessments designed by scholars. The new study sought to center the Cherokee students’ perspectives.

“There’s been so much erasure of Native American people historically that we don’t often get to hear their stories and their voices, especially compared to other racial and ethnic minority groups,” Hoffman said. “This research brings Native voices to the table, literally, by asking them about these issues.”

After defining stereotypes – ideas about a group that may or may not be true for all people or things in that group – the researchers asked an open-ended question: “Please list the stereotypes that you have heard about Cherokee or Native American people.”

The 212 students offered more than 300 responses, which the researchers grouped into 19 categories. More than 13% of the responses referenced positive cultural traditions, from dancing and basket-making to wearing traditional clothes. Substance abuse was cited third most often, in 10% of responses, and was among those that echoed negative stereotypes identified in prior research, such as being “savage,” unintelligent or violent. Some stereotypes were categorized as historical distortions likely influenced by media, referencing scalping, buffalo and smallpox. Some were neutral (“we braid our hair”).

Tied for the most frequently cited stereotype – not identified in prior research – was what the students called “per cap.” That’s a reference to the Eastern Band of Cherokees receiving per capita shares of casino revenue, which the teens framed as an entitlement or privilege: “we are rich because we get per cap,” “big money,” “Cherokees get paid to do nothing.” That finding would not be generalizable to all Native Americans – more than half of recognized tribal nations do not have casinos – but highlights the importance of local context in studying stereotypes, the researchers said.

Additional findings showed differences in school context, with public school students where Cherokees were the largest ethnic minority reporting more stereotypes, including a majority of the “per cap” references. Most sixth-graders did not list any stereotypes, indicating a more limited understanding of the concept. The numbers increased in seventh grade and were highest in eighth grade, suggesting that interventions might be effective in that age range, because that is when stereotype awareness emerges. No significant differences were found in how boys or girls reported stereotypes.

“This study provides one of the first accounts of adolescents’ spontaneous generation of stereotypes about Native Americans,” the researchers wrote, “and shows that early adolescence is a formative time.”

The research was supported by the National Science Foundation.

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Journal

Youth & Society

DOI

10.1177/0044118X2513746 

Subject of Research

People

Article Title

Early Adolescent Cherokees’ Reports of Stereotypes About Native Americans

 

Health and economic air quality co-benefits of stringent climate policies

CMCC Foundation - Euro-Mediterranean Center on Climate Change

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Key Messages

• Avoiding temperature overshoot through stringent climate policies such as net-zero could prevent 207,000 premature deaths by 2030.

• Such policies could also avoid $2,269 billion USD in economic damages, roughly 2% of 2020 global GDP.

• Benefits are particularly large in China and India, where air pollution and population density are high, and substantial emission reductions are predicted.

Air pollution is one of the world’s leading health risks, contributing to nearly 1 in 8 deaths globally. A new study published in Science Advances by the Euro-Mediterranean Center on Climate Change (CMCC) shows that stringent climate policies designed to avoid temporarily exceeding 1.5°C warming could prevent hundreds of thousands of premature deaths while avoiding trillions of dollars in economic damages.

The researchers used a global source-receptor air pollution model to estimate the impacts of net-zero pathways on air quality, health, and economic costs. They found that avoiding temperature overshoot could prevent 207,000 premature deaths and reduce $2,269 billion USD in damages by 2030, equivalent to roughly 2% of 2020’s global GDP. The benefits are particularly notable in regions with high population density and pollution, such as China and India.

“This work shows, in a comprehensive and robust way, that pursuing short-term temperature stabilization is worthwhile,” says CMCC scientist Lara Aleluia Reis. “Not only does it reduce climate risks, it also brings significant health benefits by improving air quality.”

The study is the first to quantify the air pollution co-benefits of limiting short-term temperature overshoot. By considering multiple scenarios, uncertainties, and regional variations, the research provides robust evidence that climate mitigation policies offer substantial dual benefits: reducing greenhouse gas emissions and saving lives through cleaner air.

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Journal

Science Advances

DOI

10.1126/sciadv.adu7590 

Eighty-five years of big tree history available in one place for the first time

US National Champion Tree Program historical documents and registers date back to 1940

University of Tennessee Institute of Agriculture

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image: 

The timeline of registers for the National Champion Tree Program dates back to 1940 and goes through the present day including species such as the National Champion Kentucky Yellowwood that is growing in New Hampshire. 

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Credit: Photo courtesy National Champion Tree Program.

Whether strolling through the woods or taking a rest from outdoor labors, autumn is a time when people contemplate the value of our trees and forests. The curious can now also explore the historical documents of the nation’s biggest trees dating back to the 1940s online, in one place, for the first time. The National Champion Tree Program at the University of Tennessee Institute of Agriculture has compiled historical records dating back to the program’s inception.

“We are thrilled to release this compilation of more than 80 years of big tree history,” says Jaq Payne, director of the National Champion Tree Program at the UT Institute of Agriculture School of Natural Resources. “These registers are a time capsule, showing us past monarchs of nature and how people have written about big trees in the past.” The registers are listed by year with some featuring different milestones such as the 50th anniversary in 1990 or the first online version to replace the print version in 2010, which was not well received by big tree fans. The records include notes about changes in the registers over time along with messages and letters.

“When this program started in the early 1940s, tree-lovers were voicing concerns about massive deforestation due to war efforts, and some early recognition of pests and diseases,” Payne adds. “Now, around 85 years later, our forests and trees continue to face threats of a different kind — an abundance of pests and pathogens, storms of increasing intensity and frequency, and pressures from thoughtless and ecologically unsound development.” Along with collecting data on big trees, the program works with communities, government agencies, universities and conservation groups on preserving them in urban and rural landscapes.

Payne hopes the compilation shows how big trees connect people to the past and the future. “Not only are they living witnesses to hundreds, sometimes thousands, of years of history, but when properly cared for, their lifespans can extend far beyond us into the lives of our grandchildren’s grandchildren,” Payne notes. “Our choices today determine what our landscape will look like in 100 years.”

The release of the historical documents comes as the program marks two years at the University of Tennessee after moving from American Forests in 2023. People can find the latest register from 2024 at the end of the historical registers’ timeline. If you know a potential tree for future registers, the program is still taking nominations through December 1.

The UTIA School of Natural Resources focuses on a mastery learning approach, emphasizing practical, hands-on experiences. The school’s faculty, staff and students advance the science and sustainable management of our natural resources through various programs of the UT Institute of Agriculture (UTIA).

UTIA is comprised of the Herbert College of Agriculture, UT College of Veterinary Medicine, UT AgResearch and UT Extension. Through its land-grant mission of research, teaching and extension, the University of Tennessee Institute of Agriculture touches lives and provides Real. Life. Solutions. to Tennesseans and beyond. utia.tennessee.edu.

 

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Method of Research

Literature review