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

Sinnakannu, J. R., Lee, K. L., Cheng, S., Li, J., Yu, M., Tan, S. P., Ong, C. C. H., Li, H., Than, H., Anczukow-Camarda, O., Krainer, A. R., Roca, X., Rozen, S. G., Iqbal, J., Yang, H., Chuah, C., Ong, S. T. (February 2020) SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia, 34 (7). pp. 1787-1798. ISSN 0887-6924

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.

Item Type:	Paper
Subjects:	diseases & disorders > inflammation > cytokines diseases & disorders > cancer > drugs and therapies > imatinib diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:	Krainer, Adrian R.
Communities:	CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Krainer lab
Depositing User:	Adrian Gomez
Date:	12 February 2020
Date Deposited:	14 Feb 2020 19:40
Last Modified:	29 Jun 2021 17:44
PMCID:	PMC7682023
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39059

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