MedElevator Войти в исследования
← Поиск публикаций

DOI 10.1038/s41586-023-05806-1

Медицинская библиотека · Nature · 2023

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Weinstock Joshua S, Gopakumar Jayakrishnan, Burugula Bala Bharathi, Uddin Md Mesbah, Jahn Nikolaus, Belk Julia A, Bouzid Hind, Daniel Bence, Miao Zhuang, Ly Nghi, Mack Taralynn M, Luna Sofia E, Prothro Katherine P, Mitchell Shaneice R, Laurie Cecelia A, Broome Jai G, Taylor Kent D, Guo Xiuqing, Sinner Moritz F, von Falkenhausen Aenne S, Kääb Stefan, Shuldiner Alan R, O'Connell Jeffrey R, Lewis Joshua P, Boerwinkle Eric, Barnes Kathleen C, Chami Nathalie, Kenny Eimear E, Loos Ruth J F, Fornage Myriam, Hou Lifang, Lloyd-Jones Donald M, Redline Susan, Cade Brian E, Psaty Bruce M, Bis Joshua C, Brody Jennifer A, Silverman Edwin K, Yun Jeong H, Qiao Dandi, Palmer Nicholette D, Freedman Barry I, Bowden Donald W, Cho Michael H, DeMeo Dawn L, Vasan Ramachandran S, Yanek Lisa R, Becker Lewis C, Kardia Sharon L R, Peyser Patricia A, He Jiang, Rienstra Michiel, Van der Harst Pim, Kaplan Robert, Heckbert Susan R, Smith Nicholas L, Wiggins Kerri L, Arnett Donna K, Irvin Marguerite R, Tiwari Hemant, Cutler Michael J, Knight Stacey, Muhlestein J Brent, Correa Adolfo, Raffield Laura M, Gao Yan, de Andrade Mariza, Rotter Jerome I, Rich Stephen S, Tracy Russell P, Konkle Barbara A, Johnsen Jill M, Wheeler Marsha M, Smith J Gustav, Melander Olle, Nilsson Peter M, Custer Brian S, Duggirala Ravindranath, Curran Joanne E, Blangero John, McGarvey Stephen, Williams L Keoki, Xiao Shujie, Yang Mao, Gu C Charles, Chen Yii-Der Ida, Lee Wen-Jane, Marcus Gregory M, Kane John P, Pullinger Clive R, Shoemaker M Benjamin, Darbar Dawood, Roden Dan M, Albert Christine, Kooperberg Charles, Zhou Ying, Manson JoAnn E, Desai Pinkal, Johnson Andrew D, Mathias Rasika A, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Blackwell Thomas W, Abecasis Goncalo R, Smith Albert V, Kang Hyun M, Satpathy Ansuman T, Natarajan Pradeep, Kitzman Jacob O, Whitsel Eric A, Reiner Alexander P, Bick Alexander G, Jaiswal Siddhartha

СтатьяПоддержка NIH: внешняя программаПоддержка службы здравоохранения СШАПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Для цитирования: Weinstock Joshua S, Gopakumar Jayakrishnan, Burugula Bala Bharathi, Uddin Md Mesbah, Jahn Nikolaus, Belk Julia A, Bouzid Hind, Daniel Bence, Miao Zhuang, Ly Nghi, Mack Taralynn M, Luna Sofia E, Prothro Katherine P, Mitchell Shaneice R, Laurie Cecelia A, Broome Jai G, Taylor Kent D, Guo Xiuqing, Sinner Moritz F, von Falkenhausen Aenne S, Kääb Stefan, Shuldiner Alan R, O'Connell Jeffrey R, Lewis Joshua P, Boerwinkle Eric, Barnes Kathleen C, Chami Nathalie, Kenny Eimear E, Loos Ruth J F, Fornage Myriam, Hou Lifang, Lloyd-Jones Donald M, Redline Susan, Cade Brian E, Psaty Bruce M, Bis Joshua C, Brody Jennifer A, Silverman Edwin K, Yun Jeong H, Qiao Dandi, Palmer Nicholette D, Freedman Barry I, Bowden Donald W, Cho Michael H, DeMeo Dawn L, Vasan Ramachandran S, Yanek Lisa R, Becker Lewis C, Kardia Sharon L R, Peyser Patricia A, He Jiang, Rienstra Michiel, Van der Harst Pim, Kaplan Robert, Heckbert Susan R, Smith Nicholas L, Wiggins Kerri L, Arnett Donna K, Irvin Marguerite R, Tiwari Hemant, Cutler Michael J, Knight Stacey, Muhlestein J Brent, Correa Adolfo, Raffield Laura M, Gao Yan, de Andrade Mariza, Rotter Jerome I, Rich Stephen S, Tracy Russell P, Konkle Barbara A, Johnsen Jill M, Wheeler Marsha M, Smith J Gustav, Melander Olle, Nilsson Peter M, Custer Brian S, Duggirala Ravindranath, Curran Joanne E, Blangero John, McGarvey Stephen, Williams L Keoki, Xiao Shujie, Yang Mao, Gu C Charles, Chen Yii-Der Ida, Lee Wen-Jane, Marcus Gregory M, Kane John P, Pullinger Clive R, Shoemaker M Benjamin, Darbar Dawood, Roden Dan M, Albert Christine, Kooperberg Charles, Zhou Ying, Manson JoAnn E, Desai Pinkal, Johnson Andrew D, Mathias Rasika A, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Blackwell Thomas W, Abecasis Goncalo R, Smith Albert V, Kang Hyun M, Satpathy Ansuman T, Natarajan Pradeep, Kitzman Jacob O, Whitsel Eric A, Reiner Alexander P, Bick Alexander G, Jaiswal Siddhartha. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.. Nature. 2023. DOI: 10.1038/s41586-023-05806-1.

Предметные рубрики MeSH

AnimalsHumansMiceAllelesClonal HematopoiesisGenome-Wide Association StudyHematopoiesisHematopoietic Stem CellsMutationPromoter Regions, GeneticRepressor ProteinsDNA Methyltransferase 3AProto-Oncogene ProteinsDNA-Binding ProteinsDioxygenases
Подготовка и перевод публикации
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

Тип публикации указан по данным источника. Уровень доказательности автоматически не присваивается.