The combination of ruxolitinib and Bcl-2/Mcl-1 inhibitors has a synergistic effect on leukemic cells carrying a SPAG9::JAK2 fusion.
Humans
Child
STAT5 Transcription Factor
/ genetics
Myeloid Cell Leukemia Sequence 1 Protein
/ genetics
Oncogene Proteins, Fusion
/ genetics
Interleukin-3
/ metabolism
Janus Kinase 2
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ genetics
Phosphorylation
Tyrosine
/ metabolism
Adaptor Proteins, Signal Transducing
/ metabolism
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
11
06
2021
accepted:
13
07
2022
revised:
26
06
2022
pubmed:
26
7
2022
medline:
17
12
2022
entrez:
25
7
2022
Statut:
ppublish
Résumé
JAK2 rearrangements can occur in Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). Here, we performed functional analysis of the SPAG9::JAK2 fusion, which was identified in a pediatric patient with Ph-like ALL, to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9::JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9::JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly upregulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9::JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9::JAK2, but not SPAG9::JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9::JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9::JAK2 fusion.
Identifiants
pubmed: 35879405
doi: 10.1038/s41417-022-00511-z
pii: 10.1038/s41417-022-00511-z
doi:
Substances chimiques
ruxolitinib
82S8X8XX8H
STAT5 Transcription Factor
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Oncogene Proteins, Fusion
0
Interleukin-3
0
Janus Kinase 2
EC 2.7.10.2
Proto-Oncogene Proteins c-bcl-2
0
Tyrosine
42HK56048U
SPAG9 protein, human
0
Adaptor Proteins, Signal Transducing
0
JAK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1930-1938Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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