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Chronic myelogenous leukemia

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

Leukemia volume 34, pages 1787–1798 (2020)Cite this article

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Abstract

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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Fig. 1: SRSF1 is upregulated in CD34+ CML progenitors.
Fig. 2: SRSF1 is upregulated by BCR-ABL1 and extrinsic cytokine signaling.
Fig. 3: Elevated SRSF1 levels confer cytokine independence in hematopoietic cells and impaired imatinib sensitivity in CML cells.
Fig. 4: Upregulated SRSF1 levels antagonize imatinib-related gene expression via a nonsplicing function of SRSF1.
Fig. 5: Schematic depicting genes in the PLC signaling pathway.
Fig. 6: Targeting PKC signaling rescues SRSF1-mediated impaired imatinib responses.
Fig. 7: SRSF1 levels correlate with imatinib response in CP CML patients.
Fig. 8

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Acknowledgements

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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Authors and Affiliations

  1. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Singapore

    Joanna R. Sinnakannu, Kian Leong Lee, Shanshan Cheng, Mengge Yu, Siew Peng Tan, Steven G. Rozen, Charles Chuah & Sin Tiong Ong

  2. Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore

    Shanshan Cheng & Steven G. Rozen

  3. Cancer Science Institute of Singapore, Singapore, Singapore

    Jia Li & Henry Yang

  4. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore

    Clara Chong Hui Ong & Jabed Iqbal

  5. Health Services Research Unit, Singapore General Hospital, Singapore, Singapore

    Huihua Li

  6. Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore

    Huihua Li

  7. Department of Haematology, Singapore General Hospital, Singapore, Singapore

    Hein Than, Charles Chuah & Sin Tiong Ong

  8. The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    Olga Anczuków-Camarda

  9. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Adrian R. Krainer

  10. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

    Xavier Roca

  11. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    Sin Tiong Ong

  12. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Sin Tiong Ong

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  1. Joanna R. Sinnakannu
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Contributions

JRS designed and performed experiments for cloning, western blots, quantitative PCR, and colony formation. MGY and SPT performed experiments for cloning, western blots, and qPCR. KLL performed the Fluidigm experiments for validation of alternative splicing isoforms. SC, JL, KLL, SR, and HY analyzed the RNA-sequencing data for gene expression and ASEs. CC and TH provided the primary CML samples. CO and JI performed the immunohistochemistry (IHC) staining and scoring. JH performed statistical analysis on the IHC scoring by CO and JI. OA-C, XR, and ARK provided experimental advice and essential reagents. STO supervised the project, and JRS prepared figures and wrote the manuscript which was approved by all authors.

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Correspondence to Sin Tiong Ong.

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Supplementary information

Supp Table 1: Short hair pin sequences

Supp Table 2: Primer list

Supp Table 3: SRSF1 IHC Clinical data

Supp Table 4: Statistical comparison between good responders and poor responders

Supp Table 5: Normalized log counts from cultured chronic phase and normal bone marrow from RNA-sequencing analysis

41375_2020_732_MOESM6_ESM.xlsx

Supp Table 6: List of detected alternative splicing events from K562 cells with SRSF1 overexpression vs vector in DMSO and IM conditions

41375_2020_732_MOESM7_ESM.xlsx

Supp Table 7: Differential alternative splicing event analysis of K562 cells with SRSF1 overexpression vs vector control in DMSO

41375_2020_732_MOESM8_ESM.xlsx

Supp Table 8: Differential alternative splicing event analysis of K562 cells with SRSF1 overexpression vs vector control in IM

Supp Table 9: Fluidigm validation for K562 cells with SRSF1 overexpression vs vector control in DMSO and IM conditions

Supp Table 10: Normalized log counts from K562 overexpressing SRSF1 and treated with IM from RNA-sequencing analysis

41375_2020_732_MOESM11_ESM.xlsx

Supp Table 11: List of significant and differential genes from analysis of K562 cells with SRSF1 overexpression vs vector control in DMSO

41375_2020_732_MOESM12_ESM.xlsx

Supp Table 12: List of significant and differential genes from analysis of K562 cells with SRSF1 overexpression vs vector control in IM

Supp Table 13: Genes in IPA biological processes from K562 cells with SRSF1 overexpression vs vector control in DMSO

Supp Table 14: Genes in IPA biological processes from 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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