Shin, Ji Eun Kim, Soo-Hyun MinGyu Kong Kim, Hwa-Ryeon Yoon, Sungmin Kee, Kyung-Mi Kim, Jung Ah Kim, Dong Hyeon Park, So Yeon Park, Jae Hyung Kim, Hongtae No, Kyoung Tai Lee, Han-Woong Gee, Heon Yung Hong, Seunghee Guan, Kun-Liang Roe, Jae-Seok Lee, Hyunbeom Kim, Dong-Wook Park, Hyun Woo 2024-01-12T06:32:51Z 2024-01-12T06:32:51Z 2023-11-13 2023-11 1476-4598 https://pubs.kist.re.kr/handle/201004/79769 Background Although 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. Methods We 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. Results We 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. Conclusion Here, 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. English BioMed Central Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia Article 10.1186/s12943-023-01837-4 1 Molecular Cancer, v.22, no.1 Molecular Cancer 22 1 Y scie scopus 001099915000002 Biochemistry & Molecular Biology Oncology Biochemistry & Molecular Biology Oncology Article EXPRESSION PATHWAY ROLES CML YAP FLT3 Drug resistance Hippo-YAP/TAZ pathway Blast phase Ponatinib Midostaurin CML AML Cancer CD36