Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Abstract

Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-␤-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-␤-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is com-

Analysis of GATA1 mutations and leukemogenesis in newborns with Down syndrome

“…These data are consistent with the frequencies of 78% by Alford et al (2011), 74% by Cabelof et al (2009), 83% by Hitzler et al (2003) and 100% by Wechsler et al (2002).…”

“…Acquired mutations in exon 2 of the hematopoietic transcription factor GATA1 mapped at Xp11.23 are consistently present in the affected cells of children with TMD and ML-DS, leading to expression of N-terminally truncated GATA1s protein (Wechsler et al, 2002;Cabelof et al, 2009). These GATA1 alterations are somatic and are therefore no longer detectable in remission samples (Ahmed et al, 2004).…”

“…In about 60% of cases, TMD resolves spontaneously within the first 3 months of life (Massey et al, 2006;Kanezaki et al, 2010). However, approximately 20% of children diagnosed with TMD will develop ML-DS, after 2 to 3 years of TMD spontaneous remission, which does not regress without chemotherapy (Mundschau et al, 2003;Cabelof et al, 2009).…”

Acute leukemia in children with Down syndrome

“…Chromosome 21-localized genes, including cystathionine-β-synthase (CBS) and zinc-copper superoxide dismutase (SOD1), are linked to abnormal intracellular folate metabolism, uracil accumulation and increased oxidative stress leading to DNA damage. 13 Past studies have demonstrated that the high event-free survival rates of Down syndrome patients with AMkL are related to increased in vitro sensitivity of Down syndrome megakaryoblasts to cytarabine (ara-C) and daunorubicin, 14 due in part to the presence of GATA1 mutations. The relationship between GATA1 mutations and outcome is highlighted by the lower frequency of GATA1 mutations in Down syndrome AML patients greater than 4 years of age, who have significantly lower event-free survival (<35%) and increased relapse rates compared to the majority of Down syndrome AML patients.…”

Transient myeloproliferative disordes in a newborns with Down Syndrome

“…İkinci tetiği çeken faktörler ise hala tanım-lanabilmiş değildir (5,6). Klinik olarak GMPH gelişmesi durumunda GATA-1 mutasyon analizi yapma imkanı varsa tanı koydurucudur (5,6,(10)(11)(12)(13)(14). Biz GATA-1 mutasyonuna bakma imkanı-mız olmadığından bakamadık.…”