Analysis of GATA1 mutations and leukemogenesis in newborns with Down syndrome

Abstract

ABSTRACT. It has been reported that patients with Down syndrome (DS) frequently develop transient myeloproliferative disorder (TMD) and less commonly myeloid leukemia in DS (ML-DS). We examined the pathogenetic relationship of these conditions with somatic mutations of the GATA1 gene in children with both TMD and ML-DS. To determine the incidence of GATA1 mutations in a cohort of DS patients and the applicability of these mutations as a clonal marker to detect minimal residual disease, we screened 198 samples of 169 patients with DS for mutations in GATA1 exon 2 by direct sequencing. Novel mutations were detected in four of the 169 DS patients (2 with TMD and 2 with ML-DS). We examined spontaneous remission and response to therapy in TMD and ML-DS patients and concluded that 4631 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 12 (4): 4630-4638 (2013) Screening for GATA1 mutations in newborns with Down syndrome these mutations can be used as stable markers in PCR analysis to monitor these events.

Cases of transient abnormal myelopoiesis

“…Генетические события в бластных клетках при ТАМ [7]. По последним представлениям первым звеном в развитии ТАМ является наличие трисомии 21-й хромосомы в бластных клетках (первый «удар»).…”

“…Genetic events in blast cells in TAM [7]. According to the latest ideas, the first link in the development of TAM is the presence of trisomy 21 in blast cells (first "hit").…”

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 S expression

“…In this context, based on the evidence that altered miRNA expression profiles are tumour-initiating events and a common hallmark of haematological malignancies [28], it has been hypothesized that HSA21complete or partial trisomy could promote over-expression of different miRNAs cooperating with GATA-1 S in the pathogenesis of AMKL. Interestingly, a link was found between a set of HSA21-encoded miRNAs (miR-99a, let-7c, miR-155, miR-125b-2) and leukaemogenesis [29][30][31]. Particularly, T21dependent miR-125b-2 over-expression was found to have synergistic effects with GATA-1 S to promote proliferation and self-renewal of fetal myeloid cells.…”

Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production

“…A transient myeloproliferative disorder with immature MK features (impaired maturation of MKs) is seen exclusively in fetuses and neonates with Down syndrome and GATA1 mutations indicating that thrombopoietin (TPO)-independent pathways may play a critical role in neonatal/fetal MK maturation [22, 24, 25]. …”