Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia

Abstract

Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS).Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P ‫؍‬ .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.

Unique Myeloid Leukemias in Young Children with Down Syndrome: Cell Origin, Association with Hematopoietic Microenvironment and Leukemogenesis

“…Consistent with this finding, it has been described that expression of GATA1s is decreased in vivo in murine mature megakaryocytes carrying a GATA1 mutation that results in the production of GATA1s equivalent to the protein products of GATA1 mutations in DS-related leukemias (Majewski et al, 2006). Kanezaki et al (2010) showed that protein levels of GATA1s in TL blasts differ depending on the sites of mutations and its quantitative differences are significantly associated with patient prognosis and the risk of developing AMKL-DS. These data suggest that protein levels of GATA1s may also be important in the biology of DS-related leukemic cells.…”

“…Several recent studies have shown activating mutations of the Janus kinase 3 (JAK3) gene, which encodes for a non-receptor tyrosine kinase, in some patients with TL and AMKL-DS (De Vita et al, 2007;Kiyoi et al, 2007;Klusmann et al, 2007), but these mutations were present in both TL and AMKL-DS and, therefore, are not likely involved in disease progression from TL to AMKL-DS. Concerning the evolution of AMKL-DS, Kanezaki et al (2010) have recently demonstrated that the expression levels of GATA1s protein are associated with the type of GATA1 mutations in TL; low expression of GATA1s is caused by mutations introducing premature termination codon (PTC) at the 5' side of exon 2 or after codon 84 on exon 3 whereas high expression of GATA1 is associated with mutations causing loss of the first methionine, splicing error or introduction of PTC at the 3' side of exon 2, and that GATA1s low mutations in TL are significantly associated with higher risk of developing AMKL-DS. The mechanism by which AMKL-DS evolves from minor clones of cells with GATA1 mutations is currently one of the main areas of research in DS-associated leukemias.…”

Evolution of myeloid leukemia in children with Down syndrome

“…Collectively, although both GATA1 dysfunction and GATA1s expression are important in the development of TAM, GATA1 dysfunction alone does not appear to be sufficient, and it may be overexpression of GATA1s that contributes to the development of DS-related myeloid disorders. Interestingly, although how GATA1s contributes to the TAM phenotype remains unclear, GATA1 mutation type and GATA1s expression levels are significantly associated with a risk of progression to ML-DS [45,48].…”

Pediatric Acute Myeloid Leukemia

“…(Chen, et al 2010, Klusmann, et al 2010a, Klusmann, et al 2010b Of interest, a recent paper shows that lower protein expression of GATA1s predicts a higher chance of ML-DS development after TL. (Kanezaki, et al 2010) Current efforts in TL are focused on 2 aspects: 1) Treatment of children with symptomatic TL to avoid TL-related deaths, which may occur from either fluid overload, organomegaly and high WBC, or from liver failure which is believed to result from cytokines produced by the leukemic blasts infiltrating the liver. (Klusmann, et al 2008) Treatment can consist of (repetitive) courses of low dose cytarabine (Al Ahmari, et al 2006), and 2) the potential to avoid clonal evolution to ML-DS by treating children with low clearance of TL as assessed by MRD measurements at pre-defined time-points.…”