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白血病前期状态下的细胞癌变：驱动因素与防御机制

Cellular carcinogenesis in preleukemic conditions:drivers and defenses.

作者信息

Ueda Koki, Ikeda Kazuhiko

机构信息

Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University.

出版信息

Fukushima J Med Sci. 2024 Jan 27;70(1):11-24. doi: 10.5387/fms.2023-17. Epub 2023 Nov 11.

DOI:10.5387/fms.2023-17
PMID:37952978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10867434/
Abstract

Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/β-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.

摘要

急性髓系白血病（AML）起源于白血病前期状态。我们已经研究了典型白血病前期、骨髓增殖性肿瘤和克隆性造血的发病机制。白血病前期状态下的造血干细胞都存在复发性驱动突变；额外的突变会引发进一步的恶性转化，导致AML发病。虽然基因改变被认为是恶性转化的主要原因，但非基因因素也参与疾病进展。在这篇综述中，我们聚焦于一种非组蛋白染色质蛋白，即高迁移率族AT钩2（HMGA2），以及一种生理性p53抑制剂，即小鼠双微体X（MDMX）。HMGA2主要通过微小RNA失调或多梳蛋白成分突变而过度表达，并通过破坏干细胞特征引发白血病前期克隆的扩增。MDMX在髓系恶性肿瘤中因剪接平衡改变而过度表达。MDMX通过抑制p53和WNT/β-连环蛋白信号通路的p53非依赖性激活，诱导白血病前期向白血病转化。我们还讨论了如何针对这些非基因因素进行白血病预防治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/9c79fb3443e1/2185-4610-70-011-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/c1d9fbd9bfc2/2185-4610-70-011-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/f9b78f18b44c/2185-4610-70-011-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/9c79fb3443e1/2185-4610-70-011-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/c1d9fbd9bfc2/2185-4610-70-011-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/f9b78f18b44c/2185-4610-70-011-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3453/10867434/9c79fb3443e1/2185-4610-70-011-g003.jpg

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本文引用的文献

1
Murine double minute X plays a central role in leukemic transformation and may be a promising target for leukemia prevention strategies.鼠双微体 X 在白血病转化中起核心作用，可能是预防白血病策略的一个有前途的靶点。
Exp Hematol. 2023 Jun;122:10-18. doi: 10.1016/j.exphem.2023.04.001. Epub 2023 Apr 20.
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HMGA2 expression defines a subset of human AML with immature transcriptional signature and vulnerability to G2/M inhibition.HMGA2 表达定义了具有不成熟转录特征和对 G2/M 抑制敏感的人类 AML 的一个亚群。
Blood Adv. 2022 Aug 23;6(16):4793-4806. doi: 10.1182/bloodadvances.2021005828.
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t(10;12)(q24;q15): A new cytogenetic marker in hematological malignancies.
t(10;12)(q24;q15)：血液恶性肿瘤中的一个新细胞遗传学标志物。
Cancer Genet. 2022 Jun;264-265:60-65. doi: 10.1016/j.cancergen.2022.03.004. Epub 2022 Mar 26.
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HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression.HMGA1染色质调节因子在骨髓增殖性肿瘤进展过程中诱导参与GATA2和增殖的转录网络。
Blood. 2022 May 5;139(18):2797-2815. doi: 10.1182/blood.2021013925.
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RNAi-Mediated Screen of Primary AML Cells Nominates MDM4 as a Therapeutic Target in NK-AML with Mutations.RNAi 介导的原发性急性髓细胞白血病细胞筛选提名 MDM4 作为具有突变的 NK-AML 的治疗靶点。
Cells. 2022 Mar 2;11(5):854. doi: 10.3390/cells11050854.
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Small Non-Coding RNAs in Leukemia.白血病中的小非编码RNA
Cancers (Basel). 2022 Jan 20;14(3):509. doi: 10.3390/cancers14030509.
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MicroRNAs: Regulatory Biomarkers in Acute Myeloid Leukemia and Graft Versus Host Disease.微小 RNA：急性髓系白血病和移植物抗宿主病中的调控生物标志物。
Clin Lab. 2022 Feb 1;68(2). doi: 10.7754/Clin.Lab.2021.210621.
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