Skip to main content

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

Publication ,  Journal Article
Sinnakannu, JR; Lee, KL; Cheng, S; Li, J; Yu, M; Tan, SP; Ong, CCH; Li, H; Than, H; Anczuków-Camarda, O; Krainer, AR; Roca, X; Rozen, SG ...
Published in: Leukemia
July 2020

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.

Duke Scholars

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

July 2020

Volume

34

Issue

7

Start / End Page

1787 / 1798

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Serine-Arginine Splicing Factors
  • Protein Kinase Inhibitors
  • Prognosis
  • Neoplastic Stem Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology
  • Imatinib Mesylate
  • Humans
  • Gene Expression Regulation, Neoplastic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sinnakannu, J. R., Lee, K. L., Cheng, S., Li, J., Yu, M., Tan, S. P., … Ong, S. T. (2020). SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia, 34(7), 1787–1798. https://doi.org/10.1038/s41375-020-0732-1
Sinnakannu, Joanna R., Kian Leong Lee, Shanshan Cheng, Jia Li, Mengge Yu, Siew Peng Tan, Clara Chong Hui Ong, et al. “SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.Leukemia 34, no. 7 (July 2020): 1787–98. https://doi.org/10.1038/s41375-020-0732-1.
Sinnakannu JR, Lee KL, Cheng S, Li J, Yu M, Tan SP, et al. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia. 2020 Jul;34(7):1787–98.
Sinnakannu, Joanna R., et al. “SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.Leukemia, vol. 34, no. 7, July 2020, pp. 1787–98. Pubmed, doi:10.1038/s41375-020-0732-1.
Sinnakannu JR, Lee KL, Cheng S, Li J, Yu M, Tan SP, Ong CCH, Li H, Than H, Anczuków-Camarda O, Krainer AR, Roca X, Rozen SG, Iqbal J, Yang H, Chuah C, Ong ST. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia. 2020 Jul;34(7):1787–1798.

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

July 2020

Volume

34

Issue

7

Start / End Page

1787 / 1798

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Serine-Arginine Splicing Factors
  • Protein Kinase Inhibitors
  • Prognosis
  • Neoplastic Stem Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology
  • Imatinib Mesylate
  • Humans
  • Gene Expression Regulation, Neoplastic