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Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and
myelodysplastic syndrome
#MMPMID29326122
Thivakaran A
; Botezatu L
; Hönes JM
; Schütte J
; Vassen L
; Al-Matary YS
; Patnana P
; Zeller A
; Heuser M
; Thol F
; Gabdoulline R
; Olberding N
; Frank D
; Suslo M
; Köster R
; Lennartz K
; Görgens A
; Giebel B
; Opalka B
; Dührsen U
; Khandanpour C
Haematologica
2018[Apr]; 103
(4
): 614-625
PMID29326122
show ga
Differentiation of hematopoietic stem cells is regulated by a concert of
different transcription factors. Disturbed transcription factor function can be
the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute
myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing
transcription factor regulating quiescence of hematopoietic stem cells and
differentiation of erythrocytes and platelets. Here, we show that low expression
of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML
patients. Using different models of human MDS or AML, we demonstrate that AML
development was accelerated with heterozygous loss of Gfi1b, and latency was
further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b
significantly increased the number of leukemic stem cells with upregulation of
genes involved in leukemia development. On a molecular level, we found that loss
of Gfi1b led to epigenetic changes, increased levels of reactive oxygen species,
as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate
that Gfi1b functions as an oncosuppressor in MDS and AML development.
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