A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL

作者：Haemmerling Susanne; Behnisch Wolfgang; Doerks Tobias; Korbel Jan O; Bork Peer; Moog Ute; Hentze Sabine; Grasshoff Ute; Bonin Michael; Riess Olaf; Janssen Johannes W G; Jauch Anna; Bartram Claus R; Reinhardt Dirk; Koch Karin A; Bandapalli Obul R; Kulozik Andreas E^*

来源：British Journal of Haematology, 2012, 157(2): 180-187.

DOI：10.1111/j.1365-2141.2012.09028.x

• transient myeloproliferative disorder
• GATA1
• microdeletion 15q24 syndrome
• trisomy 21
• leukaemogenesis

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%26apos;s normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2.58 similar to 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.

• 出版日期2012-4