(Press-News.org) Scientists at St. Jude Children’s Research Hospital developed a novel combination therapy approach for a leukemia subtype harboring rearrangements in the KMT2A gene. The approach overcomes the cancer’s drug resistance, without adding toxicity. The study was published today in Proceedings of the National Academy of Science.
Bromodomain and extra-terminal domain (BET) inhibitors have been shown to provide therapeutic benefits against many different cancers. However, the mechanisms governing response and resistance to this class of therapies are poorly understood.
Scientists at St. Jude conducted CRISPR screens, performing a genome-wide loss of function analysis in leukemia harboring KMT2A rearrangements. These rearrangements are often found in infants and can occur in acute lymphoblastic or myelogenous leukemia (ALL or AML).
“KMT2A rearrangements are enriched in infant leukemias which generally have a poor prognosis,” said co-corresponding author Jun J. Yang, Ph.D., St. Jude Departments of Pharmacy and Pharmaceutical Sciences and Oncology. “Over the past several decades, there has been very little progress in improving cure rates of infants with KMT2A-rearranged leukemias, so there is a clear need to develop new therapies for those patients.”
“This is one of the very few genetic abnormalities that can affect ALL and AML, which makes it very interesting from a tumor biology perspective,” Yang added.
CRISPR reveals a combination strategy
The researchers found that loss of the SPOP gene causes significant BET inhibitor resistance, which they confirmed in cell lines and xenograft mouse models. Additional CRISPR screens revealed that cells treated with BET inhibitors are sensitive to disruptions in the gene GSK3B.
Armed with this information, the researchers developed a combination therapy approach that uses both BET and GSK3 inhibitors against KMT2A mutated leukemia. The work demonstrated that the combination could impede the growth of leukemia cells.
“Our expertise in combinatorial CRISPR screens allowed us to identify resistance mechanisms, but by also doing reverse screens, we also identified the targetable options that will allow us to overcome resistance,” said co-corresponding author Chunliang Li, Ph.D., St. Jude Department of Tumor Cell Biology. “Our findings led us to a combination regimen that can reverse resistance to BET inhibition. The BET and GSK3 inhibitor combination shows remarkable efficacy but also no increase in toxicity because the GSK3 and BET inhibitors synergize, but on its own, the GSK3 inhibitor doesn’t seem to have an effect.”
The findings suggest that the combination of BET and GSK3 inhibition holds promise for further development in KMT2A-rearranged leukemias.
Authors and funding
The study’s co-first authors are Shaela Wright, Jianzhong Hu and Hong Wang of St. Jude. The study’s other authors are Marina Konopleva and Steven Kornblau, University of Texas MD Anderson Cancer Center; Rui Lu, O’Neil Comprehensive Cancer Center, University of Alabama at Birmingham; and Judith Hyle, Yang Zhang, Guoqing Du, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz and Beisi Xu of St. Jude.
The study was supported by the National Institutes of Health (NCI-5P30CA021765-37, R01 CA259480), V-Scholar Foundation fund (V2021-010), the American Cancer Society-Hasse Family Glenn Hasse-Research Scholar Grant (RSG-23-874240-01-DMC) and ALSAC, the fundraising and awareness organization of St. Jude.
Read the full text of the Proceedings of the National Academy of Science article:
Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens
Proceedings of the National Academy of Science, published April 10, 2023
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.
St. Jude Media Relations Contacts
Chelsea Bryant
Media Relations Strategist
(901) 595-0564 (Desk)
(256) 244-2048 (Cell)
chelsea.bryant@stjude.org
Michael Sheffield
Desk: (901) 595-0221
Cell: (901) 379-6072
michael.sheffield@stjude.org
media@stjude.org
END
Combination therapy overcomes BET inhibitor resistance
2023-04-11
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
Maryam Baldawi named winner of the 2023 AADOCR Gert Quigley Fellowship
2023-04-11
Alexandria, VA – The American Association for Dental, Oral, and Craniofacial Research (AADOCR) has announced Maryam Baldawi as the 2023 AADOCR Gert Quigley Government Affairs Fellow.
The Gert Quigley Fellowship is designed to familiarize graduate-level students with the federal legislative process in the context of dental, oral, and craniofacial research and the oral health care delivery system. As part of the Fellowship, Baldawi will complete a short work stay at AADOCR headquarters in Alexandria, VA. She will serve a one-year term as a voting member of AADOCR’s Government Affairs Committee and as the government affairs liaison to the AADOCR National Student ...
Parathyroidectomy shows no effect on kidney function in older adults with hyperparathyroidism
2023-04-11
1. Parathyroidectomy shows no effect on kidney function in older adults with hyperparathyroidism
Subanalysis suggests the procedure may preserve kidney function in younger patients if done early
Abstract: https://www.acpjournals.org/doi/10.7326/M22-2222
URL goes live when the embargo lifts
An emulated randomized trial performed using observational data from more than 43,000 adults with primary hyperparathyroidism found that parathyroidectomy had no estimated effect on long-term kidney function in older adults when compared to observation. However, ...
Parental knowledge and attitudes toward HIV preventive treatment for their adolescent children
2023-04-11
HIV pre-exposure prophylaxis (PrEP), a daily regimen of two medications in a single pill, could prevent many new HIV infections, especially in at-risk populations. For example, research shows PrEP could prevent around 70 percent of new HIV infections in adolescent cisgender sexual minority males (ASMM) and transgender and gender diverse adolescents (TGDA), populations that are disproportionately affected by the disease. However, despite growing awareness of PrEP among ASMM/TGDA, uptake of the treatment is still less than 5 percent.
A new study published in the journal Sexuality Research and Social Policy looks ...
Texas A&M researchers discover new circuit element
2023-04-11
Dr. H. Rusty Harris, associate professor in the Department of Electrical and Computer Engineering at Texas A&M University, has identified a new circuit element known as a meminductor.
A circuit element is an electrical component used to help direct and control the flow of electricity through an electrical circuit. The classical three are known as the resistor, capacitor and inductor. Two additional circuit elements, the memristor and the memcapacitor, were only discovered in the past 15 years. These newer circuit elements are known as the mem- versions of their classical counterparts, and their current and voltage properties are dependent ...
Endocrine Society alarmed by Texas court ruling banning mifepristone
2023-04-11
WASHINGTON—The Endocrine Society is deeply concerned about a Texas ruling that reverses the U.S. Food and Drug Administration’s (FDA) approval of mifepristone, a drug used to treat Cushing’s syndrome and to end pregnancy safely and effectively.
Last week, two conflicting federal court decisions in Texas and Washington state left access to mifepristone unclear for both the treatment of Cushing’s syndrome and for medical abortions.
The Texas court ruled to ban mifepristone, taking away the FDA's authority to regulate the safety of medications. The judge paused ...
Mint flavor makes vape juice more toxic, damaging to lungs
2023-04-11
PITTSBURGH, April 10, 2023 – Adding mint flavor to e-cigarette liquids produces more vapor particles and is associated with worse lung function in those who smoke, report researchers from the University of Pittsburgh in Respiratory Research today.
Using a specially designed robotic system that mimics the mechanics of human breathing and vaping behavior, researchers showed that commercially available e-cigarette liquids containing menthol generate a greater number of toxic microparticles compared to menthol-free juice. An accompanying analysis of patient records from a cohort of e-cigarette smokers revealed that menthol vapers took shallower breaths and ...
View interpolation networks for reproducing the material appearance of specular objects
2023-04-11
With the spread of Internet shopping nowadays, purchasing products online has become possible and common. However, in many cases, because users are presented with few photographs of products and cannot actually hold the products, they may be unable to perceive the material of the products.
In this study, we proposed view interpolation networks for reproducing material appearances. We implemented U-Net, an existing image transformation network, and a network that used additional information in the middle layer of U-Net. The networks were trained to generate images from the intermediate ...
Unrolling a rain-guided detail recovery network for singleimage deraining
2023-04-11
Rain streaks of different shapes, sizes, and directions obscure image background scenes, resulting in image degradation, including intensity fluctuation, color distortion, or even content alteration. Such degradation impairs the visual quality of an image and leads to undesirable performance of many outdoor computer vision systems that require high-quality images. Therefore, image deraining must be performed, and effective deraining methods should be developed. In this study, we addressed the problem of single-image rain removal.
We propose a novel unrolling rain-guided detail recovery network ...
Impact of coronavirus on states’ fertility rates tracked with economic, social, and political divides
2023-04-11
Experts have found that at the start of the COVID-19 outbreak in early 2020, Americans chose not to become pregnant as they grappled with stay-at-home restrictions, anxiety, and economic hardship. Now, a new study led by researchers at NYU Grossman School of Medicine shows that some states actually experienced steeper decreases in fertility than others.
The findings revealed that nine months after the pandemic began, there were 18 fewer births a month per 100,000 women of reproductive age across the U.S. compared with the year ...
A new primary care model proves effective for patients with severe mental illness
2023-04-10
CHAPEL HILL, N.C. – Over the past few years, the Department of Family Medicine and the Department of Psychiatry in UNC’s School of Medicine have been working together to spearhead the development of a new “enhanced primary care” model to provide better primary care for patients who have severe mental illnesses.
A new analysis led by Alex K. Gertner, MD, PhD, psychiatry resident at UNC Hospitals, has added further evidence that the new model is effective. Gertner found that the enhanced primary care model resulted in lower hemoglobin A1c and blood pressure for patients with severe mental illness when compared to other primary care clinics throughout ...