SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.

Leukemia 2020 Jul

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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 support an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.

Citation

Joanna R Sinnakannu, Kian Leong Lee, Shanshan Cheng, Jia Li, Mengge Yu, Siew Peng Tan, Clara Chong Hui Ong, Huihua Li, Hein Than, Olga Anczuków-Camarda, Adrian R Krainer, Xavier Roca, Steven G Rozen, Jabed Iqbal, Henry Yang, Charles Chuah, Sin Tiong Ong. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia. 2020 Jul;34(7):1787-1798