Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome

Department of Pediatrics, Division of Hematology/Oncology, Maria Fareri Children's Hospital and Westchester Medical Center, New York Medical College, Valhalla, NY 10595, USA.
Blood (Impact Factor: 10.45). 10/2007; 110(6):2128-31. DOI: 10.1182/blood-2007-01-069542
Source: PubMed


Somatic mutations in the GATA1 gene are present in almost all cases of Down syndrome (DS)-associated acute megakaryoblastic leukemia (AMKL) and transient leukemia (TL). An in utero origin of the GATA1 mutation suggests it is an early leukemogenic event. To determine the detectable incidence and clinical relevance of GATA1 mutations in DS newborns, we screened Guthrie cards from 590 DS infants for mutations in the GATA1 gene. Twenty-two (3.8%) of 585 evaluable infants harbored a predicted functional GATA1 mutation; 2 were identified exclusively within intron 1. Hispanic newborns were 2.6 times more likely to have a mutated GATA1 gene than non-Hispanics (P = .02). Two newborns with a GATA1 mutation subsequently developed AMKL, and none of the infants without a functional GATA1 mutation were reported to have developed leukemia. In addition to screening for TL, a GATA1 mutation at birth might serve as a biomarker for an increased risk of DS-related AMKL.

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Available from: Sharon R Pine, Jan 01, 2014
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    • "Mutations restricted to leukemic clones were not detectable in samples in remission. They were therefore selected and acquired, probably because they granted a clonal advantage (Pine et al., 2007; Wechsler et al., 2002). Rainis et al. (2003) reported two patients with identical GATA1 mutations in TL and subsequently in AMKL, showing that the AMKL was originated from the clone of TMD. "

    Full-text · Chapter · Dec 2011
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    • "DS-AMKL is strictly restricted to neonates, infants, or young children with DS or trisomy 21 (Hasle 2001; Klusmann et al. 2008), thus providing a unique context in which to address these issues. Five percent to 10% of DS infants develop the related, antecedent transient leukemia (DS-TL, also known as transient myeloproliferative disorder ½TMDŠ) (Pine et al. 2007). Although DS-TL resolves spontaneously in the majority of cases, 20%– 30% of patients progress to DS-AMKL within the first 4 years of life (Klusmann et al. 2008). "
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    ABSTRACT: Oncogene-mediated transformation of hematopoietic cells has been studied extensively, but little is known about the molecular basis for restriction of oncogenes to certain target cells and differential cellular context-specific requirements for oncogenic transformation between infant and adult leukemias. Understanding cell type-specific interplay of signaling pathways and oncogenes is essential for developing targeted cancer therapies. Here, we address the vexing issue of how developmental restriction is achieved in Down syndrome acute megakaryoblastic leukemia (DS-AMKL), characterized by the triad of fetal origin, mutated GATA1 (GATA1s), and trisomy 21. We demonstrate overactivity of insulin-like growth factor (IGF) signaling in authentic human DS-AMKL and in a DS-AMKL mouse model generated through retroviral insertional mutagenesis. Fetal but not adult megakaryocytic progenitors are dependent on this pathway. GATA1 restricts IGF-mediated activation of the E2F transcription network to coordinate proliferation and differentiation. Failure of a direct GATA1-E2F interaction in mutated GATA1s converges with overactive IGF signaling to promote cellular transformation of DS fetal progenitors, revealing a complex, fetal stage-specific regulatory network. Our study underscores context-dependent requirements during oncogenesis, and explains resistance to transformation of ostensibly similar adult progenitors.
    Full-text · Article · Aug 2010 · Genes & development
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    • "GATA1 mutations occur at high frequency in T21 patients (c. 4%) of all DS neonates from a recent study of 526 neonatal blood spots (Pine et al, 2007) and 25% of patients with DS-AMKL have multiple, independent GATA1 mutations (Ahmed et al, 2004). GATA1 mutations are not detected in other DS and non-DS leukaemias. "
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    ABSTRACT: Children with Down syndrome (DS) have a marked increase in susceptibility to Acute Megakaryoblastic Leukaemia (DS-AMKL) and the closely linked neonatal preleukaemic syndrome, Transient Myeloproliferative Disorder (DS-TMD). The distinct stages of DS-TMD and DS-AMKL provide an excellent tractable model to study leukaemogenesis. This review focuses on recent studies describing clinical, haematological and biological features of DS-AMKL and DS-TMD. The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS-AMKL and DS-TMD may be useful in diagnosis and assessing minimal residual disease. These findings raise the possibility of population-based screening strategies for DS-TMD and the development of treatment to eliminate the preleukaemic TMD clone to prevent DS-AMKL. Advances in our understanding of perturbed haemopoiesis in DS, the role of GATA1 and of cooperating mutations are also discussed. These findings have implications for leukaemia biology more broadly given the frequency of acquired trisomy in other human leukaemias.
    Full-text · Article · Aug 2009 · British Journal of Haematology
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