The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
15
09
2021
accepted:
20
10
2021
revised:
18
10
2021
pubmed:
10
11
2021
medline:
12
3
2022
entrez:
9
11
2021
Statut:
ppublish
Résumé
FLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta chain of IL-3, IL-5, and GM-CSF, and therefore examined its significance for FLT3-ITD-dependent oncogenic signaling and transformation. We discovered that FLT3-ITD directly binds to CSF2RB in AML cell lines and blasts isolated from AML patients. A knockdown of CSF2RB in FLT3-ITD positive AML cell lines as well as in a xenograft model decreased STAT5 phosphorylation, attenuated cell proliferation, and sensitized to FLT3 inhibition. Bone marrow from CSF2RB-deficient mice transfected with FLT3-ITD displayed decreased colony formation capacity and delayed disease onset together with increased survival upon transplantation into lethally irradiated mice. FLT3-ITD-dependent CSF2RB phosphorylation required phosphorylation of the FLT3 juxtamembrane domain at tyrosines 589 or 591, whereas the ITD insertion site and sequence were of no relevance. Our results demonstrate that CSF2RB participates in FLT3-ITD-dependent oncogenic signaling and transformation in vitro and in vivo. Thus, CSF2RB constitutes a rational treatment target in FLT3-ITD-positive AML.
Identifiants
pubmed: 34750506
doi: 10.1038/s41375-021-01462-4
pii: 10.1038/s41375-021-01462-4
pmc: PMC8885422
doi:
Substances chimiques
CSF2RB protein, human
0
Cytokine Receptor Common beta Subunit
0
Csf2rb protein, mouse
144715-98-0
FLT3 protein, human
EC 2.7.10.1
Flt3 protein, mouse
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
701-711Informations de copyright
© 2021. The Author(s).
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