Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia

IF 12.8 1区 医学 Q1 HEMATOLOGY
Xiaoman Shao, Rui Yokomori, Jolynn Zu Lin Ong, Haoqing Shen, Dennis Kappei, Leilei Chen, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda
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Abstract

The transcription factor MYB is frequently upregulated in T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy originating from T-cell precursors. Here, we demonstrate that MYB plays a crucial role by regulating genes essential for T-ALL pathogenesis. Integrative analysis reveals a long MYB isoform, ENST00000367814.8, which is dominantly expressed and confers a proliferative advantage in T-ALL cells. Rapid depletion of MYB via dTAG-mediated protein degradation affects a large number of genes, which can be classified into early response or late response genes based on their kinetics. Early response genes include many genes involved in hematopoiesis, such as TAL1, RUNX1, GATA3, IKZF2, and CXCR4. Their expression can be recovered at later time-points, suggesting the presence of a negative feedback loop mechanism. In contrast, late response genes, which are continuously downregulated after MYB depletion, includes many genes involved in cell proliferation as well as TAL1 targets, thereby affecting the cellular phenotype.

Abstract Image

Abstract Image

T 细胞急性淋巴细胞白血病中受 MYB 控制的转录调控程序。
转录因子 MYB 经常在 T 细胞急性淋巴细胞白血病(T-ALL)中上调,T-ALL 是一种源自 T 细胞前体的血液恶性肿瘤。在这里,我们证明了 MYB 通过调控 T-ALL 发病机制中的重要基因发挥着至关重要的作用。整合分析揭示了一种长的 MYB 异构体 ENST00000367814.8,它在 T-ALL 细胞中显性表达并赋予细胞增殖优势。通过 dTAG 介导的蛋白降解快速消耗 MYB 会影响大量基因,根据其动力学可将其分为早期反应基因和晚期反应基因。早期反应基因包括许多参与造血的基因,如 TAL1、RUNX1、GATA3、IKZF2 和 CXCR4。它们的表达可在后期时间点恢复,这表明存在负反馈循环机制。相反,晚期反应基因在 MYB 缺失后会持续下调,其中包括许多参与细胞增殖的基因以及 TAL1 靶点,从而影响细胞表型。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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