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造血干细胞衰老和白血病发生潜能中的性别依赖性差异。

Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.

作者信息

Zhang Chunxiao, Hao Taisen, Bortoluzzi Alessia, Chen Min-Hsuan, Wu Xiwei, Wang Jinhui, Ermel Richard, Kim Young, Chen Shiuan, Chen WenYong

机构信息

Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.

Amgen, Thousand Oaks, CA, USA.

出版信息

Oncogene. 2025 Jan;44(2):64-78. doi: 10.1038/s41388-024-03197-9. Epub 2024 Nov 1.

DOI:10.1038/s41388-024-03197-9
PMID:39487323
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11706783/
Abstract

Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia. These disparities are underlined by sex-differentiated HSC aging characteristics across the population, single-cell, and molecular levels. The HSC population expanded significantly with aging and longevity in males, but this occurred to a much lesser degree in aging females that instead expanded committed progenitors. Aging male HSCs are more susceptible to BCR-ABL1 transformation with faster development of chronic myeloid leukemia (CML) than female HSCs. Additionally, the loss of the aging regulator Sirt1 inhibited CML development in aging male but not female mice. Our results showed for the first time that sex-differentiated HSC aging impacts hematopoiesis, leukemogenesis, and certain gene functions. This discovery provides insights into understanding age-dependent hematological diseases and sex-targeted strategies for the treatment and prevention of certain blood disorders and cancer.

摘要

性别会影响许多生物学结果，但性别如何影响造血干细胞（HSC）衰老和血液系统疾病却鲜为人知。使用年轻动物模型来研究与年龄相关的疾病的广泛做法进一步使这些问题变得复杂。利用老年和长寿的BALB/c小鼠模型，我们发现衰老小鼠在发生髓系偏斜、贫血和白血病方面表现出与衰老人类相似的性别依赖性差异。这些差异在群体、单细胞和分子水平上由性别分化的造血干细胞衰老特征所突显。雄性小鼠的造血干细胞群体随着衰老和寿命延长而显著扩大，但衰老雌性小鼠的这种情况要少得多，相反，衰老雌性小鼠中定向祖细胞会扩大。衰老的雄性造血干细胞比雌性造血干细胞更容易受到BCR-ABL1转化的影响，慢性髓性白血病（CML）的发展也更快。此外，衰老调节因子Sirt1的缺失抑制了衰老雄性小鼠而非雌性小鼠的慢性髓性白血病发展。我们的结果首次表明，性别分化的造血干细胞衰老会影响造血、白血病发生和某些基因功能。这一发现为理解年龄依赖性血液疾病以及治疗和预防某些血液疾病和癌症的性别针对性策略提供了见解。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/f2f0f397b613/41388_2024_3197_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/1a85a860e5e4/41388_2024_3197_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/6a86b3dde3ca/41388_2024_3197_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/209f11381de8/41388_2024_3197_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/385db3c05803/41388_2024_3197_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/3cac4c9a1349/41388_2024_3197_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/858c74128f6b/41388_2024_3197_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ec/11706783/f2f0f397b613/41388_2024_3197_Fig7_HTML.jpg
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