Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/144283
Title: SRSF1-MEDIATED TYROSINE KINASE INHIBITOR RESISTANCE IN CHRONIC MYELOID LEUKAEMIA
Authors: SINNAKANNU JOANNA RAJESWARY
Keywords: SRSF1, CML, CD34+, Splicing factors, TKI-resistance
Issue Date: 11-Apr-2018
Citation: SINNAKANNU JOANNA RAJESWARY (2018-04-11). SRSF1-MEDIATED TYROSINE KINASE INHIBITOR RESISTANCE IN CHRONIC MYELOID LEUKAEMIA. ScholarBank@NUS Repository.
Abstract: Tyrosine kinase inhibitors (TKIs) which inhibit BCR-ABL1 kinase activity control but do not cure chronic myeloid leukemia (CML), suggesting the existence of BCR-ABL1-independent factors that preserve CML leukemic stem cells (LSCs). Using RNA-sequencing, we identified differentially expressed splicing factors in CD34+ CML stem and progenitor cells compared to healthy controls. Among them, we found SRSF1 to be consistently increased at both transcript and protein levels. Using a variety of mouse and human cells, increased SRSF1 expression was found to be a result of both BCR-ABL1- and cytokine-mediated signalling. Functionally, SRSF1 overexpression led to partial TKI-resistance and cytokine-independence in cell lines. Conversely, depleting SRSF1 impaired colony formation and cell proliferation. Mechanistically, we find that elevated SRSF1 levels antagonize genes involved in signal transduction, implying the activation of several signal transduction pathways for survival. These results are supported by the activation of multiple signalling pathways including STAT5 and mTOR signalling. In summary, we find SRSF1 to be upregulated in CD34+ CP CML progenitors in a BCR-ABL1- and cytokine-dependent manner, and that elevated levels promote TKI-resistance. Taken together, our data suggest that SRSF1 acts a downstream effector of cytokine-mediated TKI-resistance in CP CML-LSCs.
URI: http://scholarbank.nus.edu.sg/handle/10635/144283
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