Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q.
Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q.
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缺失5Q产生的分子特征的病理生理和临床意义。
DOI：
10.1016/j.ebiom.2022.104059
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发表时间：
2022-06
期刊：
影响因子：
11.1
通讯作者：
Maciejewski JP
中科院分区：
文献类型：
--
作者：
Adema V;Palomo L;Walter W;Mallo M;Hutter S;La Framboise T;Arenillas L;Meggendorfer M;Radivoyevitch T;Xicoy B;Pellagatti A;Haferlach C;Boultwood J;Kern W;Visconte V;Sekeres M;Barnard J;Haferlach T;Solé F;Maciejewski JP
5号染色体[del(5q)]长臂缺失引起的单倍体功能不全(HI)及其伴随的杂合性丢失可能是del(5q)髓系肿瘤(MN)的关键致病因素，尽管del(5q)的后果尚未阐明。在这里，我们研究了388例del(5q)和841例二倍体MN[82%骨髓增生异常综合征(MDS)]的突变、基因表达和临床表型。DEL(5q)为创立型(预后较好)或继发性HIT(先于TP53突变)。通过对57个HI标记基因的贝叶斯预测分析，我们建立了区分del(5q)和二倍体的最小del(5q)基因特征。模拟del(5q)特征的二倍体病例群总体上支持del(5q)基因在MDS发病机制中的整体重要性。Del(5q)患者中的亚群指向HI基因固有的患者内异质性。潜在的克隆扩张驱动是“HI驱动”基因(如CSNK1A1、CTNNA1、TCERG1)和促凋亡“HI抗驱动”(如RPS14、Pura、SIL1)之间的平衡的结果。残留的基本克隆性扩张驱动允许选择加速器突变，如TP53(命名不良)和CSNK1A1突变(预后较好)，它们克服了促凋亡基因(例如p21、BAD、Bax)，导致克隆性扩张。综上所述，我们描述了del(5q)MN识别决定del(5q)患者临床病程的关键基因、基因簇和克隆层级的全貌。托尔斯滕·哈弗拉克白血病诊断基金会。美国国家卫生研究院(NIH)授予R35 HL135795、R01HL123904、R01 HL118281、R01 HL128425、R01 HL132071，以及爱德华·P·埃文斯基金会的赠款。
Haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified. Here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)]. Del(5q) resulted as founder (better prognosis) or secondary hit (preceded by TP53 mutations). Using Bayesian prediction analyses on 57 HI marker genes we established the minimal del(5q) gene signature that distinguishes del(5q) from diploid cases. Clusters of diploid cases mimicking the del(5q) signature support the overall importance of del(5q) genes in the pathogenesis of MDS in general. Sub-clusters within del(5q) patients pointed towards the inherent intrapatient heterogeneity of HI genes. The underlying clonal expansion drive results from a balance between the “HI-driver” genes (e.g., CSNK1A1, CTNNA1, TCERG1) and the proapoptotic “HI-anti-drivers” (e.g., RPS14, PURA, SIL1). The residual essential clonal expansion drive allows for selection of accelerator mutations such as TP53 (denominating poor) and CSNK1A1 mutations (with a better prognosis) which overcome pro-apoptotic genes (e.g., p21, BAD, BAX), resulting in a clonal expansion. In summary, we describe the complete picture of del(5q) MN identifying the crucial genes, gene clusters and clonal hierarchy dictating the clinical course of del(5q) patients. Torsten Haferlach Leukemia Diagnostics Foundation. US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, and a grant from Edward P. Evans Foundation.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
50.3
作者：
Schneider RK;Ademà V;Heckl D;Järås M;Mallo M;Lord AM;Chu LP;McConkey ME;Kramann R;Mullally A;Bejar R;Solé F;Ebert BL
通讯作者：
Ebert BL
影响因子：
30.8
作者：
Makishima H;Yoshizato T;Yoshida K;Sekeres MA;Radivoyevitch T;Suzuki H;Przychodzen B;Nagata Y;Meggendorfer M;Sanada M;Okuno Y;Hirsch C;Kuzmanovic T;Sato Y;Sato-Otsubo A;LaFramboise T;Hosono N;Shiraishi Y;Chiba K;Haferlach C;Kern W;Tanaka H;Shiozawa Y;Gómez-Seguí I;Husseinzadeh HD;Thota S;Guinta KM;Dienes B;Nakamaki T;Miyawaki S;Saunthararajah Y;Chiba S;Miyano S;Shih LY;Haferlach T;Ogawa S;Maciejewski JP
通讯作者：
Maciejewski JP
影响因子：
45.3
作者：
Jerez, Andres;Gondek, Lukasz P.;Maciejewski, Jaroslaw P.
通讯作者：
Maciejewski, Jaroslaw P.
影响因子：
3.6
作者：
Maciejewski, Jaroslaw P.;Padgett, Richard A.;Mueller-Tidow, Carsten
通讯作者：
Mueller-Tidow, Carsten