ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
23 03 2023
23 03 2023
Historique:
received:
08
12
2022
accepted:
28
02
2023
revised:
27
02
2023
entrez:
24
3
2023
pubmed:
25
3
2023
medline:
28
3
2023
Statut:
epublish
Résumé
Deletion of ABL1 was detected in a cohort of hematologic malignancies carrying AML1-ETO and NUP98 fusion proteins. Abl1-/- murine hematopoietic cells transduced with AML1-ETO and NUP98-PMX1 gained proliferation advantage when compared to Abl1 + /+ counterparts. Conversely, overexpression and pharmacological stimulation of ABL1 kinase resulted in reduced proliferation. To pinpoint mechanisms facilitating the transformation of ABL1-deficient cells, Abl1 was knocked down in 32Dcl3-Abl1ko cells by CRISPR/Cas9 followed by the challenge of growth factor withdrawal. 32Dcl3-Abl1ko cells but not 32Dcl3-Abl1wt cells generated growth factor-independent clones. RNA-seq implicated PI3K signaling as one of the dominant mechanisms contributing to growth factor independence in 32Dcl3-Abl1ko cells. PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1-/- cells when compared to the Abl1 + /+ counterparts. Since the role of ABL1 in DNA damage response (DDR) is well established, we also tested the inhibitors of ATM (ATMi), ATR (ATRi) and DNA-PKcs (DNA-PKi). AML1-ETO;Abl1-/- and NUP98-PMX1;Abl1-/- cells were hypersensitive to DNA-PKi and ATRi, respectively, when compared to Abl1 + /+ counterparts. Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors.
Identifiants
pubmed: 36959186
doi: 10.1038/s41408-023-00810-0
pii: 10.1038/s41408-023-00810-0
pmc: PMC10036529
doi:
Substances chimiques
AML1-ETO fusion protein, human
0
Core Binding Factor Alpha 2 Subunit
0
nuclear pore complex protein 98
0
Nuclear Pore Complex Proteins
0
Nup98 protein, human
0
Oncogene Proteins, Fusion
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
RUNX1 Translocation Partner 1 Protein
0
Proto-Oncogene Proteins c-abl
EC 2.7.10.2
Prrx1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
42Subventions
Organisme : NCI NIH HHS
ID : R01 CA216813
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244044
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237286
Pays : United States
Informations de copyright
© 2023. The Author(s).
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