SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia
| Autor: | Adrian R. Krainer, Hein Than, Jia Li, Sin Tiong Ong, Siew Peng Tan, Steven G. Rozen, Huihua Li, Kian Leong Lee, Clara Chong Hui Ong, Mengge Yu, Jabed Iqbal, Henry Yang, Joanna R. Sinnakannu, Xavier Roca, Olga Anczuków-Camarda, Shanshan Cheng, Charles Chuah |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Article 03 medical and health sciences 0302 clinical medicine Bone Marrow hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive medicine Biomarkers Tumor Tumor Cells Cultured Humans Progenitor cell neoplasms Protein Kinase Inhibitors Serine-Arginine Splicing Factors business.industry Myeloid leukemia Imatinib Hematology medicine.disease Prognosis Gene Expression Regulation Neoplastic Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure Cytokine Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Imatinib Mesylate Neoplastic Stem Cells Cytokines Bone marrow business Tyrosine kinase medicine.drug |
| Zdroj: | Leukemia |
| Popis: | Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI-resistance. Among extrinsic factors, cytokine-mediated TKI-resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34(+) chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine-independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34(+) CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1, were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34(+) CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data supports an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML. |
| Databáze: | OpenAIRE |
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