Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia

• Published in: Communications biology Vol. 5; no. 1; pp. 396 - 15
• Main Authors: Wang, Zhiqiang, Zhang, Chunxiao, Warden, Charles David, Liu, Zheng, Yuan, Yate-Ching, Guo, Chao, Wang, Charles, Wang, Jinhui, Wu, Xiwei, Ermel, Richard, Vonderfecht, Steven L., Wang, Xiuli, Brown, Christine, Forman, Stephen, Yang, Yaling, James You, M., Chen, WenYong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/109; 13/2; 13/31; 13/89; 14/63; 38/77; 42/41; 45/22; 45/29; 45/90; 631/532/2118/1542; 631/532/7; 692/4028/67/1990/283/1897; 82/29; Aging; Aging - genetics; Animals; Biology; Biomedical and Life Sciences; Bone marrow; Bone marrow transplantation; Genotype & phenotype; Hematological diseases; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Leukemia; Leukemia - genetics; Leukemia - metabolism; Life Sciences; Mice; Oxidative metabolism; Phenotype; Phenotypes; Protein biosynthesis; Protein turnover; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Stem cell transplantation; Stem cells; Therapeutic targets; Transcription factors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03340-w

Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients. The majority of secondary and tertiary BMT recipients of aging wild type donor cells developed B/myeloid mixed phenotype acute leukemia (MPAL), which was markedly inhibited by Sirt1 knockout. SIRT1 inhibition also reduced the growth and survival of human B/myeloid MPAL cells. Sirt1 knockout suppressed global gene activation in old HSCs, prominently the genes regulating protein synthesis and oxidative metabolism, which may involve multiple downstream transcriptional factors. Our results demonstrate an unexpected role of SIRT1 in promoting HSC aging and age-dependent MPAL and suggest SIRT1 may be a new therapeutic target for modulating functions of aging HSCs and treatment of MPAL. Studies employing serial bone marrow transplantation in mice show that Sirt1 knockout improves quiescence maintenance and function of aging hematopoietic stem cells. Sirt1 loss also prevents the development of age-dependent B/myeloid mixed phenotype acute leukemia.