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

Rika Kanezaki, Tsutomu Toki, Kiminori Terui, Gang Xu, Ru Nan Wang, Akira Shimada, Asahito Hama, Hirokazu Kanegane, Kiyoshi Kawakami, Mikiya Endo, Daisuke Hasegawa, Kazuhiro Kogawa, Souichi Adachi, Yasuhiko Ikeda, Shotaro Iwamoto, Takashi Taga, Yoshiyuki Kosaka, Seiji Kojima, Yasuhide Hayashi, Etsuro Ito

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 classi-fied 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.

Original languageEnglish
Pages (from-to)4631-4638
Number of pages8
JournalBlood
Volume116
Issue number22
DOIs
Publication statusPublished - Nov 25 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kanezaki, R., Toki, T., Terui, K., Xu, G., Wang, R. N., Shimada, A., Hama, A., Kanegane, H., Kawakami, K., Endo, M., Hasegawa, D., Kogawa, K., Adachi, S., Ikeda, Y., Iwamoto, S., Taga, T., Kosaka, Y., Kojima, S., Hayashi, Y., & Ito, E. (2010). Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: Mutation classes correlate with progression to myeloid leukemia. Blood, 116(22), 4631-4638. https://doi.org/10.1182/blood-2010-05-282426