Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -β, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.

造血系统内的分子改变会影响细胞寿命和与年龄相关的骨髓干细胞疾病（如急性髓系白血病（AML）和慢性髓系白血病（CML））的发展。衰老小鼠造血干细胞 (HSC) 中 SIRT7 表达的减少会导致寿命缩短和增殖增加。在这项研究中，我们研究了健康人中 SIRT7 表达的年龄相关变化以及 AML 和 CML 的相关病理机制。健康人白细胞中 SIRT7 的表达以年龄依赖性方式下降。在 AML 和 CML 患者中也检测到低 SIRT7 mRNA 水平。随着积极的治疗反应，SIRT7 表达增加，但当患者病情进展或复发时，SIRT7 表达减少。对 AML (FLT3-ITD) 或 CML (BCR-ABL) 驱动突变的药物抑制也可恢复细胞系和患者样本中的 SIRT7 水平。此外，在PMA介导的THP-1细胞的单核细胞分化过程中，SIRT7的表达随着时间的推移而增加。 THP-1 细胞中 SIRT7 过表达导致分化标记物表达增加。 BCR-ABL、FLT3-ITD 和分化相关的 SIRT7 表达通常受到与 SIRT7 启动子内两个不同 C/EBP 结合位点结合的 C/EBPα、-β 和 -ε 的正向调节。 SIRT7对于人类造血细胞的衰老和长寿非常重要。它可能充当肿瘤抑制因子，并有可能作为监测骨髓干细胞疾病治疗反应的通用生物标志物。