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

  title={SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia},
  author={Joanna Rajeswary Sinnakannu and Kian Leong Lee and Shanshan Cheng and Jia Li and Mengge Yu and Siew Peng Tan and Clara Chong Hui Ong and Huihua Li and Hein Than and Olga Anczuk{\'o}w-Camarda and Adrian R. Krainer and Xavier Roca and Steven G. Rozen and Jabed Iqbal and Henry Yang and Charles Chuah and Sin Tiong Ong},
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… Expand
3 Citations
Understanding the hematopoietic microenvironment in chronic myeloid leukemia: A concise review.
This concise review of recent findings on the composition and function of the bone marrow microenvironment in CML, and their importance in the progression of the disease and treatment resistance is summarized. Expand
Transcriptome Analysis Reveals High Similarities between Adult Human Cardiac Stem Cells and Neural Crest-Derived Stem Cells
High similarities are found between adult human cardiac stem cells and neural crest-derived stem cells from the nasal cavity, which include a shared relation to the neural crest. Expand
Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome.
The current understanding of the connections between splicing and cancer is discussed, with a focus on the most recent findings. Expand


Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors
It is shown for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), whereas Gab2 knockdown or haploinsufficiency leads to increased TKI sensitivity. Expand
Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance
The data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors, and Stat3 dependency was specific for cells grown in CM, providing preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment. Expand
Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.
Results suggest that in the hypoxic microenvironment, HIF1-α signaling supports LSC persistence independent of BCR-ABL1 kinase activity, and targeting HIF 1-α and its pathway components may be therapeutically important for the complete eradication of LSCs. Expand
Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.
It is reported that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy, suggesting that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR -ABL will not eliminate C ML stem cells. Expand
A role for FOXO1 in BCR–ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia
It is concluded that elevated FOXO1 contributes to BCR–ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with B CR–ABl1 inhibition may represent a novel therapeutic approach. Expand
BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance
Five Philadelphia-chromosome positive cell lines are introduced as TKI-resistance models that are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Expand
BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients.
Evidence is provided that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance. Expand
Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment
The role of LSCs and stem cell niche in relation to response to pharmacological treatments and the interaction with the bone marrow microenvironment is focused on. Expand
Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition
It is shown that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR, and mTOR inhibition as an alternative therapeutic approach in TKI-resistantCML cells is highlighted. Expand
Secretion of IL‐1β from imatinib‐resistant chronic myeloid leukemia cells contributes to BCR–ABL mutation‐independent imatinib resistance
Elevated IL‐1β production from TKI‐resistant K562R cells may contribute to TKI resistance by increasing cell viability and promoting cell migration. Expand