IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.
IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.
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DOI：
10.1371/journal.pone.0040934
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Martinelli G
中科院分区：
文献类型：
--
作者：
Iacobucci I;Iraci N;Messina M;Lonetti A;Chiaretti S;Valli E;Ferrari A;Papayannidis C;Paoloni F;Vitale A;Storlazzi CT;Ottaviani E;Guadagnuolo V;Durante S;Vignetti M;Soverini S;Pane F;Foà R;Baccarani M;Müschen M;Perini G;Martinelli G
IKAROS（IKZF 1）的缺失经常发生在B细胞前体急性淋巴细胞白血病（B-ALL）中，但它们影响发病机制的机制尚不清楚。为了解决这个问题，通过单核苷酸多态性（SNP）阵列对144例成人B-ALL患者（106例BCR-ABL 1阳性和38例已知分子重排阴性的B-ALL患者）进行IKZF 1缺失筛查;然后对这些患者的子队列（44%）进行基因表达谱分析。BCR-ABL 1阳性B-ALL病例中IKZF 1完全或部分缺失的频率高于BCR-ABL 1阴性B-ALL病例（分别为75%和58%，p = 0.04）。 比较携带IKZF 1缺失的患者与没有缺失的患者的基因表达特征，显示出独特的特征，其特征在于B细胞谱系和DNA修复基因的下调以及参与细胞周期、JAK-STAT信号传导和干细胞自我更新的基因的上调。通过染色质免疫沉淀和荧光素酶报告基因测定，我们在体内和体外证实了这些发现，表明Ikaros缺失的同种型缺乏直接调节签名中的一大组基因的能力，例如IGLL 1，BLK，EBF 1，MSH 2，BUB 3，ETV 6，YES 1，CDKN 1A（p21），CDKN 2C（p18）和MCL 1。在这里，我们首次鉴定并验证了IKZF 1特异性控制的分子通路，揭示了IKZF 1在B-ALL发病机制中的作用。
Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling. Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1. Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
51.1
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
5.3
作者：
MOLNAR, A;GEORGOPOULOS, K
通讯作者：
GEORGOPOULOS, K
DOI：
10.1073/pnas.95.2.657
发表时间：
1998-01-20
影响因子：
11.1
作者：
Klug, CA;Morrison, SJ;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.