A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL
A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL
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DOI：
10.1111/j.1365-2141.2012.09028.x
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发表时间：
2012-04
影响因子：
6.5
通讯作者：
Susanne Haemmerling;W. Behnisch;T. Doerks;J. Korbel;P. Bork;U. Moog;S. Hentze;U. Grasshoff;M. Bonin;O. Riess;J. W. Janssen;A. Jauch;C. Bartram;D. Reinhardt;Karin Koch;O. Bandapalli;A. Kulozik
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文献类型：
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作者：
Susanne Haemmerling;W. Behnisch;T. Doerks;J. Korbel;P. Bork;U. Moog;S. Hentze;U. Grasshoff;M. Bonin;O. Riess;J. W. Janssen;A. Jauch;C. Bartram;D. Reinhardt;Karin Koch;O. Bandapalli;A. Kulozik
新生儿的短暂性骨髓增生性疾病（TMD）和唐氏综合征（DS）儿童的急性巨核细胞白血病（AMKL）代表了白血病发生的典型模型。21号染色体基因剂量效应和X染色体转录因子GATA 1的截短突变协同作用，引发大多数患者的TMD和AMKL。在这里，我们报告的发生TMD，自发缓解，后来发展为AMKL的患者没有DS，但有明显的畸形综合征。白血病克隆的遗传分析显示体细胞三体21和截短GATA 1突变。在基因组单核苷酸多态性（SNP）阵列上对患者正常血细胞DNA的分析显示了一个从头生殖系2·58 Mb 15 q24微缺失，包括41个已知的基因，包括肿瘤抑制因子PML。对微缺失、21号染色体编码蛋白和GATA 1中包含的基因编码的蛋白进行的基因组背景分析表明，微缺失可能通过干扰涉及PML、SUMO 3和GATA 1的正常巨核细胞生成的假设调控网络的平衡来触发白血病发生。因此，15 q24微缺失可能代表了启动白血病发生的第一个遗传命中，并暗示PML和SUMO 3是TMD/AMKL中白血病发生网络的新组分。
Transient myeloproliferative disorder (TMD) of the newborn and acute megakaryoblastic leukaemia (AMKL) in children with Down syndrome (DS) represent paradigmatic models of leukaemogenesis. Chromosome 21 gene dosage effects and truncating mutations of the X‐chromosomal transcription factor GATA1 synergize to trigger TMD and AMKL in most patients. Here, we report the occurrence of TMD, which spontaneously remitted and later progressed to AMKL in a patient without DS but with a distinct dysmorphic syndrome. Genetic analysis of the leukaemic clone revealed somatic trisomy 21 and a truncating GATA1 mutation. The analysis of the patient's normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2·58 Mb 15q24 microdeletion including 41 known genes encompassing the tumour suppressor PML. Genomic context analysis of proteins encoded by genes that are included in the microdeletion, chromosome 21‐encoded proteins and GATA1 suggests that the microdeletion may trigger leukaemogenesis by disturbing the balance of a hypothetical regulatory network of normal megakaryopoiesis involving PML, SUMO3 and GATA1. The 15q24 microdeletion may thus represent the first genetic hit to initiate leukaemogenesis and implicates PML and SUMO3 as novel components of the leukaemogenic network in TMD/AMKL.