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赖氨酸甲基转移酶 SMYD2 是正常淋巴细胞发育所必需的，也是造血白血病细胞存活所必需的。

The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias.

机构信息

Department of Clinical Sciences, Colorado State University, Fort Collins, CO, 80523, USA.

Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, 80523, USA.

出版信息

Genes Immun. 2020 Feb;21(2):119-130. doi: 10.1038/s41435-020-0094-8. Epub 2020 Mar 2.

DOI:10.1038/s41435-020-0094-8
PMID:32115575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7183909/
Abstract

The five membered SET and MYND Domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and proliferation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated as an oncogene in leukemias deriving from flawed hematopoietic stem cell (HSC) differentiation. We show here that conditional SMYD2 loss disrupts hematopoiesis at and downstream of the HSC via both apoptotic loss and transcriptional deregulation of HSC proliferation and disruption of Wnt-β-Catenin signaling. Yet, previously documented SMYD2 cell cycle targets were unscathed. Turning our analysis to human leukemias, we observed that SMYD2 is highly expressed in CML, MLLr-B-ALL, AML, T-ALL, and B-ALL leukemias and its levels in B-ALL correlate with poor survival. SMYD2 knockdown results in apoptotic death and loss of anchorage-independent transformation of each of these hematopoietic leukemias. These data provide an underlying mechanism by which SMYD2 acts during normal hematopoiesis and as a proto-oncogene in leukemia.

摘要

五联体 SET 和 MYND 结构域包含的赖氨酸甲基转移酶（SMYD）家族在发育和增殖中起着关键作用。最初在心血管系统中被描述为一个成员，SMYD2 已被认为是白血病的致癌基因，来源于有缺陷的造血干细胞（HSC）分化。我们在这里表明，条件性 SMYD2 缺失通过 HSC 增殖的凋亡丧失和转录失调以及 Wnt-β-Catenin 信号转导的破坏，在 HSC 及其下游扰乱造血。然而，先前记录的 SMYD2 细胞周期靶标未受影响。我们将分析转向人类白血病，观察到 SMYD2 在 CML、MLLr-B-ALL、AML、T-ALL 和 B-ALL 白血病中高度表达，并且在 B-ALL 中的水平与不良预后相关。SMYD2 敲低导致每种造血白血病的凋亡死亡和锚定独立转化的丧失。这些数据提供了 SMYD2 在正常造血过程中以及作为白血病原癌基因发挥作用的潜在机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/9f1e13eb173a/nihms-1564243-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/253023da0d81/nihms-1564243-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/e60a6f34c267/nihms-1564243-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/9f1e13eb173a/nihms-1564243-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/bcf28ee5b583/nihms-1564243-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/84d28ee4a829/nihms-1564243-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/325cb593cf00/nihms-1564243-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/143b7f320e26/nihms-1564243-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/253023da0d81/nihms-1564243-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/e60a6f34c267/nihms-1564243-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08f1/7183909/9f1e13eb173a/nihms-1564243-f0007.jpg

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Treatment and biology of pediatric acute lymphoblastic leukemia.
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