Abstract：
Myelodysplastic syndromes (MDS) are a heterogenous collection of clonal bone marrow diseases characterized by cytopenias, abnormal karyotypes, molecular abnormalities, and dysplasia by flow cytometry and/or morphology. The progression of MDS to severe cytopenias and/or overt leukemia is associated with the accumulation of additional cytogenetic abnormalities, suggesting clonal evolution. The impact of these accumulated abnormalities on myeloid maturation and the severity of the disease is poorly understood.
Bone marrow specimens from 16 patients with cytogenetic abnormalities were flow cytometrically sorted into three myeloid populations: progenitors, immature myeloid cells, and mature myeloid cells. Fluorescence in situ hybridization analysis was performed on each to determine the distribution of chromosomal abnormalities during myeloid maturation.
Our findings revealed three distinct distributions of cytogenetic abnormalities across myeloid maturation, each of which corresponded to specific cytogenetic abnormalities. Group 1 had continuous distribution across all maturational stages and contained patients with a single cytogenetic aberration associated with good-to-intermediate prognosis; Group 2 had accumulation of abnormalities in immature cells and contained patients with high-risk monosomy 7; and Group 3 had abnormalities defining the founding clone equally distributed across maturational stages while subclonal abnormalities were enriched in progenitor cells and contained patients with multiple, non-monosomy 7, abnormalities with evidence of clonal evolution.
Our findings demonstrate that low-risk abnormalities (e.g., del(20q) and trisomy 8) occurring in the founding clone display a markedly different disease etiology, with respect to myeloid maturation, than monosomy 7 or abnormalities acquired in subclones, which result in a disruption of myeloid cell maturation in MDS.
Bone marrow specimens from 16 patients with cytogenetic abnormalities were flow cytometrically sorted into three myeloid populations: progenitors, immature myeloid cells, and mature myeloid cells. Fluorescence in situ hybridization analysis was performed on each to determine the distribution of chromosomal abnormalities during myeloid maturation.
Our findings revealed three distinct distributions of cytogenetic abnormalities across myeloid maturation, each of which corresponded to specific cytogenetic abnormalities. Group 1 had continuous distribution across all maturational stages and contained patients with a single cytogenetic aberration associated with good-to-intermediate prognosis; Group 2 had accumulation of abnormalities in immature cells and contained patients with high-risk monosomy 7; and Group 3 had abnormalities defining the founding clone equally distributed across maturational stages while subclonal abnormalities were enriched in progenitor cells and contained patients with multiple, non-monosomy 7, abnormalities with evidence of clonal evolution.
Our findings demonstrate that low-risk abnormalities (e.g., del(20q) and trisomy 8) occurring in the founding clone display a markedly different disease etiology, with respect to myeloid maturation, than monosomy 7 or abnormalities acquired in subclones, which result in a disruption of myeloid cell maturation in MDS.
摘要：
背景：骨髓增生异常综合征（MDS）是以血细胞减少为特征的克隆性骨髓疾病的异质性集合，异常核型,分子异常，和发育不良通过流式细胞术和/或形态学。MDS进展为严重的血细胞减少症和/或明显的白血病与其他细胞遗传学异常的积累有关，暗示克隆进化。这些累积的异常对髓样成熟和疾病严重程度的影响知之甚少。
方法：对16例细胞遗传学异常患者的骨髓标本进行流式细胞计数，分为三个髓系群体：祖细胞，未成熟的骨髓细胞，和成熟的骨髓细胞。对每个进行荧光原位杂交分析，以确定骨髓成熟过程中染色体异常的分布。
结果：我们的发现揭示了三种不同的细胞遗传学异常分布在骨髓成熟过程中，每个都对应于特定的细胞遗传学异常。第1组在所有成熟阶段都有连续分布，并且包含与良好到中等预后相关的单个细胞遗传学畸变的患者；第2组在未成熟细胞中积累了异常，并且包含具有7个高危单体的患者；第3组有异常，定义了在成熟阶段均匀分布的基本克隆，而亚克隆异常在祖细胞中富集，并且包含多个患者，非单体7，异常与克隆进化的证据。
结论：我们的研究结果表明，低风险异常(例如，在创始克隆中发生的del（20q）和Trisomy8）显示出明显不同的疾病病因，关于骨髓成熟，比单体7或亚克隆中获得的异常，导致MDS中骨髓细胞成熟的破坏。
方法：对16例细胞遗传学异常患者的骨髓标本进行流式细胞计数，分为三个髓系群体：祖细胞，未成熟的骨髓细胞，和成熟的骨髓细胞。对每个进行荧光原位杂交分析，以确定骨髓成熟过程中染色体异常的分布。
结果：我们的发现揭示了三种不同的细胞遗传学异常分布在骨髓成熟过程中，每个都对应于特定的细胞遗传学异常。第1组在所有成熟阶段都有连续分布，并且包含与良好到中等预后相关的单个细胞遗传学畸变的患者；第2组在未成熟细胞中积累了异常，并且包含具有7个高危单体的患者；第3组有异常，定义了在成熟阶段均匀分布的基本克隆，而亚克隆异常在祖细胞中富集，并且包含多个患者，非单体7，异常与克隆进化的证据。
结论：我们的研究结果表明，低风险异常(例如，在创始克隆中发生的del（20q）和Trisomy8）显示出明显不同的疾病病因，关于骨髓成熟，比单体7或亚克隆中获得的异常，导致MDS中骨髓细胞成熟的破坏。
