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2016 ; 6
(ä): 33165
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New insights into the Shwachman-Diamond Syndrome-related haematological disorder:
hyper-activation of mTOR and STAT3 in leukocytes
#MMPMID27658964
Bezzerri V
; Vella A
; Calcaterra E
; Finotti A
; Gasparello J
; Gambari R
; Assael BM
; Cipolli M
; Sorio C
Sci Rep
2016[Sep]; 6
(ä): 33165
PMID27658964
show ga
Shwachman-Diamond syndrome (SDS) is an inherited disease caused by mutations of a
gene encoding for SBDS protein. So far little is known about SBDS exact function.
SDS patients present several hematological disorders, including neutropenia and
myelodysplastic syndrome (MDS), with increased risk of leukemic evolution. So
far, the molecular mechanisms that underlie neutropenia, MDS and AML in SDS
patients have been poorly investigated. STAT3 is a key regulator of several
cellular processes including survival, differentiation and malignant
transformation. Moreover, STAT3 has been reported to regulate neutrophil
granulogenesis and to induce several kinds of leukemia and lymphoma. STAT3
activation is known to be regulated by mTOR, which in turn plays an important
role in cellular growth and tumorigenesis. Here we show for the first time, to
the best of our knowledge, that both EBV-immortalized B cells and primary
leukocytes obtained from SDS patients present a constitutive hyper-activation of
mTOR and STAT3 pathways. Interestingly, loss of SBDS expression is associated
with this process. Importantly, rapamycin, a well-known mTOR inhibitor, is able
to reduce STAT3 phosphorylation to basal levels in our experimental model. A
novel therapeutic hypothesis targeting mTOR/STAT3 should represent a significant
step forward into the SDS clinical practice.