| RRC ID |
74981
|
| 著者 |
Hiroki H, Ishii Y, Piao J, Namikawa Y, Masutani M, Honda H, Akahane K, Inukai T, Morio T, Takagi M.
|
| タイトル |
Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells.
|
| ジャーナル |
Sci Rep
|
| Abstract |
BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells.
|
| 巻・号 |
13(1)
|
| ページ |
7588
|
| 公開日 |
2023-5-10
|
| DOI |
10.1038/s41598-023-33852-2
|
| PII |
10.1038/s41598-023-33852-2
|
| PMID |
37165001
|
| PMC |
PMC10172294
|
| MeSH |
Animals
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl / metabolism
Interferons / pharmacology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
Leukemia, Myeloid*
Mice
Mice, Transgenic
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Poly(ADP-ribose) Polymerases
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Ribose
|
| IF |
3.998
|
| リソース情報 |
| ヒト・動物細胞 |
Rat-1(RCB1830) |
