Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome

Marianne E. Greene, Gina Mundschau, Joshua Wechsler, Michael McDevitt, Alan Gamis, Judith Karp, Sandeep Gurbuxani, Robert Arceci, John D. Crispino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Mutations in transcription factors often contribute to human leukemias by providing a block to normal differentiation. To determine whether mutations in the hematopoietic transcription factor GATA1 are associated with leukemia, we assayed for alterations in the GATA1 gene in bone marrow samples from patients with various subtypes of acute leukemia. Here we summarize our findings that GATA1 is mutated in the leukemic blasts of patients with Down syndrome acute megakaryoblastic leukemia (DS-AMKL). We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from over 75 other patients with acute leukemia or from 21 healthy individuals. Since the GATA1 mutations were restricted to DS-AMKL, we also investigated whether GATA1 was altered in the "preleukemia" of DS, transient myeloproliferative disorder (TMD). TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients. We detected GATA1 mutations in TMD blasts from every infant examined. Together, these results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD and DS-AMKL, and that mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. We hypothesize that disruption of normal GATA-1 function is an essential step in the initiation of megakaryoblastic leukemia in DS.

Original languageEnglish (US)
Pages (from-to)351-356
Number of pages6
JournalBlood Cells, Molecules, and Diseases
Volume31
Issue number3
DOIs
StatePublished - 2003

Funding

This paper is based on a presentation at a Focused Workshop on “Myeloid Development and Leukemia” sponsored by the Leukemia and Lymphoma Society in Annapolis, Maryland, May 4–7, 2003. The authors thank Drs. Michelle Le Beau and John Anastasi for advice and for contributing the photographs in Fig. 2 . This research was facilitated by a collaboration with the Children's Oncology Group and was supported, in part, by a Junior Faculty Award from the American Society of Hematology (J.D.C.) and a grant from the Aplastic Anemia and MDS International Foundation (M.G.). J.D.C. is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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