Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia.
Zhiqiang WangChunxiao ZhangCharles David WardenZheng LiuYate-Ching YuanChao GuoCharles WangJinhui WangXiwei WuRichard ErmelSteven L VonderfechtXiuli WangChristine BrownStephen J FormanYaling YangM James YouWenYong ChenPublished in: Communications biology (2022)
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.
Keyphrases
- oxidative stress
- induced apoptosis
- bone marrow
- ischemia reperfusion injury
- cell cycle arrest
- wild type
- signaling pathway
- mesenchymal stem cells
- acute myeloid leukemia
- endothelial cells
- dendritic cells
- transcription factor
- immune response
- cell death
- endoplasmic reticulum stress
- genome wide
- dna methylation
- cell therapy
- cell proliferation
- genome wide identification
- pi k akt