Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia.
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.
Kanezaki
Rika
R
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Toki
Tsutomu
T
Terui
Kiminori
K
Xu
Gang
G
Wang
Runan
R
Shimada
Akira
A
Hama
Asahito
A
Kanegane
Hirokazu
H
Kawakami
Kiyoshi
K
Endo
Mikiya
M
Hasegawa
Daisuke
D
Kogawa
Kazuhiro
K
Adachi
Souichi
S
Ikeda
Yasuhiko
Y
Iwamoto
Shotaro
S
Taga
Takashi
T
Kosaka
Yoshiyuki
Y
Kojima
Seiji
S
Hayashi
Yasuhide
Y
Ito
Etsuro
E
D017398:Alternative Splicing; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000150:complications* / Q000235:genetics; D010641:Phenotype
D050982:GATA1 Transcription Factor