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Tag: Cell Development

  • Study reveals genetic variant linked to increased risk of leukemia in Hispanic/Latino children

    Study reveals genetic variant linked to increased risk of leukemia in Hispanic/Latino children

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    Acute lymphoblastic leukemia (ALL), the most common childhood cancer, disproportionately affects children of Hispanic/Latino origin in the United States. They are 30-40% more likely to get ALL than non-Hispanic white children, but the exact genetic basis and cause of that increased risk are unknown.

    Now, a study from the Keck School of Medicine of USC has revealed a key genetic variant contributing towards the increased risk, as well as details about the biological basis of ALL. The team used genetic fine-mapping analysis, a statistical method that allows researchers to disentangle the separate effects of genetic variants in a region of the genome. They identified a variant found at a relatively high frequency in people of Hispanic/Latino origin that increases ALL risk by around 1.4 times. The study, funded in part by the National Institutes of Health, was just published in the journal Cell Genomics.

    “Combined with the fact that around 30% of Hispanic/Latino people in the United States carry this gene variant, but it’s basically absent in people of predominantly European ancestry, we think it’s an important contributor to the increased ALL risk among this group,” said the study’s lead author, Adam de Smith, PhD, an assistant professor of population and public health sciences and a member of the USC Norris Comprehensive Cancer Center at the Keck School of Medicine, as well as a scholar of the Leukemia & Lymphoma Society.

    The researchers also performed tests to better understand how the variant, located on the IKZF1 gene, which underlies B-cell development, relates to ALL through its influence on the development of B-cells, a type of white blood cell known to be disrupted by the disease.

    Together, the analyses in our study provide the statistical, biological and evolutionary insights behind this increased risk, and may ultimately aid scientists working to develop screening tools and therapies for ALL.”


    Charleston Chiang, PhD, associate professor of population and public health sciences and associate director of the Center of Genetic Epidemiology at the Keck School of Medicine and study’s co-senior author

    The genetic basis of leukemia risk

    To pinpoint the genetic basis of the elevated ALL risk Hispanic/Latino children face, the researchers analyzed genetic data from the California Cancer Records Linkage Project. Their dataset included 1,878 Hispanic/Latino children in California with ALL and 8,411 without the condition; 1,162 non-Hispanic white children with ALL and 57,341 without; and 318 East Asian children with ALL and 5,017 without. 

    The research team focused on the IKZF1 gene, known to relate to ALL but never before linked with ethnic risk disparities. Using genetic fine-mapping analysis, they independently analyzed each position along the gene-;known as a single nucleotide polymorphism (SNP)-;to determine whether having a certain variant increased ALL risk.

    They found three independent SNPs linked to higher ALL incidence, one of which was present in about 30% of people of Hispanic/Latino origin in the U.S. and less than 1% of people of primarily European origin. Although overall risk for the disease is low across all racial/ethnic groups, children with that gene variant, located at SNP rs76880433, were 1.44 times as likely to develop ALL as children without the variant. 

    The genetic ancestry of most Hispanics/Latinos can be traced to Europe, Africa, and Indigenous America. Further investigation revealed that the risk variant was specifically linked with Indigenous American ancestry and may have become more common in this group because it conferred a selective advantage at some point in human history.

    Next, the Keck School of Medicine team partnered with co-senior author Vijay Sankaran, MD, PhD, an associate professor of pediatrics at Harvard Medical School and attending physician at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, to conduct a series of experiments to better understand how the genetic variant at IKZF1 increases risk for ALL.

    One experiment analyzed chromatin accessibility, a test which indicates how fully a given gene can be expressed. The researchers found that the risk variant reduced chromatin accessibility, preventing IKZF1 proteins from being fully expressed.

    Sankaran and his team also conducted experiments with stem cells, finding that “knocking out” the IKZF1 gene caused B-cell development to stall in its early stages.

    “Looking at all of this together, we think that the risk variant is reducing IKZF1 expression,” de Smith said. “By doing so, it’s keeping B-cells in a more immature state, which would increase ALL risk by giving the cells more chance to develop mutations that could eventually lead to overt leukemia.”

    Leukemia screening and treatment

    The new insights about IKZF1 bring researchers one step closer to developing effective screening tools to predict who may develop ALL, but more research is needed. In addition, the findings provide important clues about potential ways to treat the disease, for instance by progressing B-cell development after it stalls.

    “We also need to understand whether this variant is associated with different patient outcomes, such as the risk of relapse or chances of survival, and why that might be,” de Smith said.

    He and his colleagues also hope to explore whether the newly identified risk variant helps explain the even higher risk of ALL among Hispanic/Latino adolescents and young adults, who are more than twice as likely to get the disease than people who are non-Hispanic white.

    About this research

    In addition to de Smith, Chiang and Sankaran, the study’s other authors are Soyoung Jeon, Jalen Langie, Tsz-Fung Chan, Steven Gazal, Nicholas Mancuso and Joseph Wiemels from the Center for Genetic Epidemiology and the USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC; Lara Wahlster, Susan Black, Liam Cato, Soumyaa Mazumder and Fulong Yu from Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute; Linda Kachuri from the Stanford University School of Medicine; Nathan Nakatsuka from the New York Genome Center; Guangze Xia from the Guangzhou National Laboratory, Guangzhoi, China; Wenjian Yang and Jun Yang from St. Jude Children’s Research Hospital, Memphis; Celeste Eng, Donglei Hu, Esteban Gonzalez Burchard and Elad Ziv from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; Catherine Metayer from the School of Public Health, University of California, Berkeley; and Xiaomei Ma from the Yale School of Public Health.

    This work was supported by the National Institutes of Health [R01CA262263, R01CA155461, R00CA246076, R35GM142783, R01DK103794, R01CA265726]; the New York Stem Cell Foundation; and the Dana-Farber Cancer Institute Presidential Priorities Initiative.

    Source:

    Keck School of Medicine of USC

    Journal reference:

    de Smith, A. J., et al. (2024) A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell Genomics. doi.org/10.1016/j.xgen.2024.100526.

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  • Unlocking the secrets of T follicular helper cells for better treatment strategies

    Unlocking the secrets of T follicular helper cells for better treatment strategies

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    T follicular helper cells (Tfh) are essential for strong antibody-mediated reactions of our immune system during infections and vaccinations. However, if they get out of control, this can cause diseases such as autoimmunity, allergies or cancer. Researchers from the University Hospital Bonn (UKB) and the Cluster of Excellence ImmunoSensation at the University of Bonn investigated the underlying mechanisms of Tfh cell development in a mouse model and thus decoded their internal networking. They hope that this will lead to new strategies for the development of highly effective vaccines and new therapies to combat various diseases. The results have now been published in the renowned journal Science Immunology.

    T follicular helper cells (Tfh cells) are a specialized subgroup within the so-called CD4+ T helper cells in the immune system. Their main task is to assist the B cells in the immune defense. They are essential for the generation of highly effective antibodies. Tfh cells therefore play a decisive role in protecting against and fighting infections. “Although Tfh cells were first described over 20 years ago, there is still no reliable protocol for their generation in cell culture,” says co-first author Dr. Yinshui Chang, former postdoctoral researcher at the University of Bonn at the UKB, describing the motivation to take a closer look at the process in the mouse model.

    The transforming growth factor TGF-β is a cytokine. This is a group of proteins that initiates and regulates the growth and differentiation of cells. The Bonn team led by Prof. Dr. Dirk Baumjohann has now discovered that this signaling molecule induces strong protein expression of both the transcription factor Bcl6 and the chemokine receptor CXCR5, which are characteristic of Tfh cells. The latter plays an important role in the targeted migration of Tfh cells into the vicinity of B cells.

    We were able to show that the Tfh cells induced by TGF-β in cell culture are quite similar to the Tfh cells generated in a living organism. They provide crucial help for B cells.”


    Luisa Bach, co-first author, doctoral student at the University of Bonn at the UKB

    Transcription factor c-Maf controls the fate of T helper cells

    Using a new method based on CRISPR gene scissors, the international team led by the Bonn researchers discovered that the production of CXCR5 induced by TGF-β is independent of the transcription factor Bcl6, but requires the transcription factor c-Maf. Remarkably, although Tfh and Th17 cells partially undergo common developmental stages, c-Maf acts as a switching factor for Tfh versus Th17 cell fates. Th17 cells are another special type of CD4+ T helper cells and play an important role in bacterial infections and autoimmune diseases.

    “Overall, our data clarify important aspects of the long-unclear prerequisites and molecular pathways for the development of Tfh cells. They also highlight the diverse functions of the transforming growth factor TGF-β. Furthermore, these data indicate that Tfh cell development in mice and humans may not be as different as we previously assumed,” says Prof. Baumjohann from the Medical Clinic III for Hematology, Oncology, Immuno-Oncology and Rheumatology at the UKB, who is a member of the Cluster of Excellence ImmunoSensation and the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn. “Importantly, our findings may have implications for the development of new therapeutic strategies that enhance Tfh cells during vaccinations and infections or inhibit them in autoimmune and allergic diseases.”

    Source:

    University Hospital Bonn (UKB) 

    Journal reference:

    Chang, Y., et al. (2024) TGF‑β specifies TFH versus TH17 cell fates of murine CD4+ T cells through c-Maf. Science Immunology. doi.org/10.1126/sciimmunol.add4818.

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  • Scientists uncover a way to “hack” neurons’ internal clocks to speed up brain cell development

    Scientists uncover a way to “hack” neurons’ internal clocks to speed up brain cell development

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    The neurons that make up our brains and nervous systems mature slowly over many months. And while this may be beneficial from an evolutionary standpoint, the slow pace makes growing cells to study neurodegenerative and neurodevelopmental diseases -; like Parkinson’s disease, Alzheimer’s disease, and autism -; in the laboratory quite challenging.

    Currently, nerve cells derived from human pluripotent stem cells take months to reach an adultlike state in the lab -; a timeline that mirrors the slow pace of human brain development. (“Pluripotent stem cells” have the potential to develop into many other kinds of cells.)

    New research led by Memorial Sloan Kettering Cancer Center (MSK), however, has uncovered a way to “hack” the cells’ internal clocks to speed up the process. And the work is shedding new light on how cells’ developmental timetables are regulated.

    “This slow pace of nerve cell development has been linked to humans’ unique and complex cognitive abilities,” says Lorenz Studer, MD, Director of MSK’s Center for Stem Cell Biology and the senior author of two recent studies published in Nature and Nature Biotechnology. “Previous research has suggested the presence of a ‘clock’ within cells that sets the pace of our neurons’ development, but its biological nature had largely remained unknown -; until now.”

    New insights into nerve cell development

    Researchers, led by study first author Gabriele Ciceri, PhD, identified an epigenetic “barrier” in the stem cells that give rise to neural cells. (“Epigenetic changes” are ones that don’t alter the DNA code.) This barrier acts as a brake on the development process and determines the rate at which the cells mature. By inhibiting the barrier, the scientists were able to speed up the neurons’ development, they reported January 31 in Nature.

    While studying brain development in mice, I was struck by how neurons progress through a series of steps in a very precise schedule. But this schedule creates a big practical challenge when working with human neurons -; what takes hours and days in the mouse requires weeks and months in human cells.”


    Dr. Gabriele Ciceri, a senior research scientist in the Studer Lab at MSK’s Sloan Kettering Institute

    Furthermore, the team showed that this rate-setting epigenetic barrier is built into neural stem cells well before they differentiate into different types of neurons. They also found higher levels of the barrier in human neurons compared with mouse neurons, which may help explain differences in the pace of cell maturation in different species.

    Uncovering foundational biology

    That such discoveries were made at a cancer center isn’t as surprising as it might seem at first blush. The Studer Lab has long focused on harnessing advances in stem cell biology to develop new therapies for degenerative diseases and cancer -; both of which are strongly associated with aging.

    Moreover, MSK has long been a leader in “basic science” research -; that is, science that seeks to build fundamental understanding of human biology.

    About half of the National Institutes of Health (NIH) budget goes to funding basic science research. And the vast majority of drugs approved by the Food and Drug Administration in recent years involved publicly funded basic research, according to the NIH.

    “All of the major advances in cancer treatment in recent years -; immune checkpoint inhibitor therapy, CAR T cell therapy, cancer vaccines -; they’re all rooted in basic research,” says Joan Massagué, PhD, Director of the Sloan Kettering Institute and MSK’s Chief Scientific Officer. “Sometimes it can take years for the medical relevance of a particular discovery to become clear.”

    ‘A valuable research tool’

    A second study, led by Studer Lab graduate students Emiliano Hergenreder and Andrew Minotti and published January 2 in Nature Biotechnology, identified a combination of four chemicals that together can promote neuronal maturation. Dubbed GENtoniK, the chemical cocktail both represses epigenetic factors that inhibit cell maturation and stimulates factors that promote it.

    Along with helping to bring neurons to an adultlike state faster in the lab, the approach holds promise for other cell types, the researchers note.

    Not only was GENtoniK shown to speed the maturation of cortical neurons (involved in cognitive functions) and spinal motor neurons (involved in movement), but the chemicals were also able to accelerate the development of several other types of cells derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).

    “The generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease,” the journal editors note in a research briefing that accompanied the study. “A major obstacle in the field arises from the fact that human neurons require many months to mature during development, making it difficult to recapitulate the process in vitro. The authors provide a valuable research tool by developing a simple drug cocktail that speeds up the maturation timeframe.”

    The findings could be particularly helpful in modeling disorders like autism that involve problems with synaptic connectivity, Dr. Studer says.

    Still, he notes, additional research is needed to develop models of neurodegenerative disorders that don’t occur until very late in life, such as Parkinson’s disease, which has long been a focus of Studer’s research.

    “Typically, a person is 60 to 70 years old when the disease begins. No baby gets Parkinson’s,” he says. “So, for those diseases, we need to be able to put the cells not just into an adult state but into an aged-like state. That’s something we’re continuing to work on.”

    Source:

    Memorial Sloan Kettering Cancer Center

    Journal references:

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