Department of Translational Hematology and Oncology Research, Lerner Research Institute Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Myelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.
EBioMedicine. 2022 Jun;80:104059. doi: 10.1016/j.ebiom.2022.104059. Epub 2022 May 23.
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.
5 号染色体长臂缺失[del(5q)]导致的杂合子不足（HI）以及随之而来的杂合子丢失，可能是 del(5q)髓系肿瘤（MN）的关键致病因素，尽管 del(5q)的后果尚未明确。
在这里，我们研究了 388 例 del(5q)与 841 例二倍体 MN[82%骨髓增生异常综合征（MDS）]病例的突变、基因表达和临床表型。
del(5q)为起始（预后较好）或继发（继发 TP53 突变）事件。使用 57 个 HI 标记基因的贝叶斯预测分析，我们建立了最小的 del(5q)基因特征，可将 del(5q)与二倍体病例区分开来。模拟 del(5q)特征的二倍体病例簇支持 del(5q)基因在 MDS 发病机制中的总体重要性。del(5q)患者中的亚簇指向 HI 基因的固有个体内异质性。
潜在的克隆扩展驱动源自“HI-驱动”基因（如 CSNK1A1、CTNNA1、TCERG1）和促凋亡“HI-抗驱动”基因（如 RPS14、PURA、SIL1）之间的平衡。残留的必需克隆扩展驱动允许选择 TP53（预后不良）和 CSNK1A1 突变（预后较好）等加速突变，这些突变克服了促凋亡基因（如 p21、BAD、BAX），从而导致克隆扩展。总之，我们描述了 del(5q)MN 的完整图像，确定了决定 del(5q)患者临床病程的关键基因、基因簇和克隆层次结构。
Torsten Haferlach 白血病诊断基金会。美国国立卫生研究院（NIH）授予 R35HL135795、R01HL123904、R01HL118281、R01HL128425、R01HL132071 以及 Edward P. Evans 基金会的一项资助。
