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@ARTICLE{MostufiZadehHaghighi:282723,
author = {G. Mostufi-Zadeh-Haghighi and P. Veratti$^*$ and K. Zodel
and G. Greve and M. Waterhouse and R. Zeiser and M. L.
Cleary and M. Lübbert$^*$ and J. Duque-Afonso},
title = {{F}unctional {C}haracterization of {T}ransforming {G}rowth
{F}actor-β {S}ignaling in {D}asatinib {R}esistance and
{P}re-{BCR}+ {A}cute {L}ymphoblastic {L}eukemia.},
journal = {Cancers},
volume = {15},
number = {17},
issn = {2072-6694},
address = {Basel},
publisher = {MDPI},
reportid = {DKFZ-2023-01849},
pages = {4328},
year = {2023},
abstract = {The multi-kinase inhibitor dasatinib has been implicated to
be effective in pre-B-cell receptor (pre-BCR)-positive acute
lymphoblastic leukemia (ALL) expressing the E2A-PBX1 fusion
oncoprotein. The TGFβ signaling pathway is involved in a
wide variety of cellular processes, including embryonic
development and cell homeostasis, and it can have dual roles
in cancer: suppressing tumor growth at early stages and
mediating tumor progression at later stages. In this study,
we identified the upregulation of the TGFβ signaling
pathway in our previously generated human
dasatinib-resistant pre-BCR+/E2A-PBX1+ ALL cells using
global transcriptomic analysis. We confirm the upregulation
of the TGFβ pathway member SMAD3 at the transcriptional and
translational levels in dasatinib-resistant
pre-BCR+/E2A-PBX1+ ALL cells. Hence, dasatinib blocks, at
least partially, TGFβ-induced SMAD3 phosphorylation in
several B-cell precursor (BCP) ALL cell lines as well as in
dasatinib-resistant pre-BCR+/E2A-PBX1+ ALL cells. Activation
of the TGFβ signaling pathway by TGF-β1 leads to growth
inhibition by cell cycle arrest at the G0/G1 stage, increase
in apoptosis and transcriptional changes of SMAD-targeted
genes, e.g. c-MYC downregulation, in pre-BCR+/E2A-PBX1+ ALL
cells. These results provide a better understanding about
the role that the TGFβ signaling pathway plays in
leukemogenesis of BCP-ALL as well as in secondary drug
resistance to dasatinib.},
keywords = {B-cell precursors (Other) / acute lymphoblastic leukemia
(Other) / dasatinib (Other) / drug resistance (Other) /
transforming growth factor-β signaling pathway (Other)},
cin = {FR01},
ddc = {610},
cid = {I:(DE-He78)FR01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37686604},
pmc = {pmc:PMC10486903},
doi = {10.3390/cancers15174328},
url = {https://inrepo02.dkfz.de/record/282723},
}