Cited 0 times in
Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 지헌영 | - |
dc.date.accessioned | 2024-05-30T06:46:40Z | - |
dc.date.available | 2024-05-30T06:46:40Z | - |
dc.date.issued | 2023-11 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/199328 | - |
dc.description.abstract | BackgroundAlthough the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.MethodsWe generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.ResultsWe reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.ConclusionHere, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies. | - |
dc.description.statementOfResponsibility | open | - |
dc.language | English | - |
dc.publisher | BioMed Central | - |
dc.relation.isPartOf | MOLECULAR CANCER | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.subject.MESH | Animals | - |
dc.subject.MESH | Blast Crisis* / drug therapy | - |
dc.subject.MESH | Blast Crisis* / genetics | - |
dc.subject.MESH | Blast Crisis* / pathology | - |
dc.subject.MESH | Drug Resistance, Neoplasm / genetics | - |
dc.subject.MESH | Fusion Proteins, bcr-abl / genetics | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics | - |
dc.subject.MESH | Mice | - |
dc.subject.MESH | Protein Kinase Inhibitors / pharmacology | - |
dc.subject.MESH | Signal Transduction | - |
dc.subject.MESH | fms-Like Tyrosine Kinase 3 / metabolism | - |
dc.title | Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Pharmacology (약리학교실) | - |
dc.contributor.googleauthor | Ji Eun Shin | - |
dc.contributor.googleauthor | Soo-Hyun Kim | - |
dc.contributor.googleauthor | Mingyu Kong | - |
dc.contributor.googleauthor | Hwa-Ryeon Kim | - |
dc.contributor.googleauthor | Sungmin Yoon | - |
dc.contributor.googleauthor | Kyung-Mi Kee | - |
dc.contributor.googleauthor | Jung Ah Kim | - |
dc.contributor.googleauthor | Dong Hyeon Kim | - |
dc.contributor.googleauthor | So Yeon Park | - |
dc.contributor.googleauthor | Jae Hyung Park | - |
dc.contributor.googleauthor | Hongtae Kim | - |
dc.contributor.googleauthor | Kyoung Tai No | - |
dc.contributor.googleauthor | Han-Woong Lee | - |
dc.contributor.googleauthor | Heon Yung Gee | - |
dc.contributor.googleauthor | Seunghee Hong | - |
dc.contributor.googleauthor | Kun-Liang Guan | - |
dc.contributor.googleauthor | Jae-Seok Roe | - |
dc.contributor.googleauthor | Hyunbeom Lee | - |
dc.contributor.googleauthor | Dong-Wook Kim | - |
dc.contributor.googleauthor | Hyun Woo Park | - |
dc.identifier.doi | 10.1186/s12943-023-01837-4 | - |
dc.contributor.localId | A03971 | - |
dc.relation.journalcode | J03200 | - |
dc.identifier.eissn | 1476-4598 | - |
dc.identifier.pmid | 37932786 | - |
dc.subject.keyword | AML | - |
dc.subject.keyword | Blast phase | - |
dc.subject.keyword | CD36 | - |
dc.subject.keyword | CML | - |
dc.subject.keyword | Cancer | - |
dc.subject.keyword | Drug resistance | - |
dc.subject.keyword | FLT3 | - |
dc.subject.keyword | Hippo-YAP/TAZ pathway | - |
dc.subject.keyword | Midostaurin | - |
dc.subject.keyword | Ponatinib | - |
dc.contributor.alternativeName | Gee, Heon Yung | - |
dc.contributor.affiliatedAuthor | 지헌영 | - |
dc.citation.volume | 22 | - |
dc.citation.number | 1 | - |
dc.citation.startPage | 177 | - |
dc.identifier.bibliographicCitation | MOLECULAR CANCER, Vol.22(1) : 177, 2023-11 | - |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.