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.
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This work was supported by grants from the National Medical Council Singapore (NMRC/CSA/0051/2013 and NMRC/CIRG/1404/2014).
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The authors declare that they have no conflict of interest.
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Supp Table 6: List of detected alternative splicing events from K562 cells with SRSF1 overexpression vs vector in DMSO and IM conditions
Supp Table 7: Differential alternative splicing event analysis of K562 cells with SRSF1 overexpression vs vector control in DMSO
Supp Table 8: Differential alternative splicing event analysis of K562 cells with SRSF1 overexpression vs vector control in IM
Supp Table 11: List of significant and differential genes from analysis of K562 cells with SRSF1 overexpression vs vector control in DMSO
Supp Table 12: List of significant and differential genes from analysis of K562 cells with SRSF1 overexpression vs vector control in IM
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Sinnakannu, J.R., Lee, K.L., Cheng, S. et al. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia 34, 1787–1798 (2020). https://doi.org/10.1038/s41375-020-0732-1
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