Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling

Kuepper, Maja Kim; Bütow, Marlena; Herrmann, Oliver; Ziemons, Janine; Chatain, Nicolas; Maurer, Angela; Kirschner, Martin; Maié, Tiago; Costa, Ivan G.; Eschweiler, Jörg; Koschmieder, Steffen; Brümmendorf, Tim H.; Müller‐Newen, Gerhard; Schemionek, Mirle

doi:10.1038/s41375-019-0427-7

Cited by 39 publications

(36 citation statements)

References 67 publications

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“…Canonical STAT3 function involves phosphorylation‐dependent dimerization followed by nuclear translocation to activate transcription. However, while extrinsic TKI resistance mediated by the bone marrow microenvironment is associated with a STAT3 transcriptional signature (Kuepper et al , ), intrinsic, cell autonomous TKI resistance is not (A.M. Eiring et al , unpublished observations), suggesting an alternative, non‐canonical function for STAT3 in drug resistance of CML. Interestingly, STAT3 has been linked to mitochondrial respiration (Lee et al , ), and was shown to activate CD36 expression in lymphoid leukaemias (Rozovski et al , ).…”

Section: Opportunities For Therapeutic Intervention and Future Directmentioning

confidence: 99%

“…Canonical STAT3 function involves phosphorylation-dependent dimerization followed by nuclear translocation to activate transcription. However, while extrinsic TKI resistance mediated by the bone marrow microenvironment is associated with a STAT3 transcriptional signature (Kuepper et al, 2019), intrinsic, cell autonomous TKI resistance is not (A.M. Eiring et al, unpublished observations), suggesting an alternative, non-canonical function for STAT3 in drug resistance of CML. Interestingly, STAT3 has been linked to mitochondrial respiration (Lee et al, 2018), and was shown to activate CD36 expression in lymphoid leukaemias AML, acute myeloid leukaemia; BCL-2, B-cell lymphoma 2; CAR-T cells, chimeric antigen receptor T cells; CML, chronic myeloid leukaemia; CMML, chronic myelomonocytic leukaemia; ETC, Electron Transport Chain; IDH, isocitrate dehydrogenase; IL-1RAP, interleukin 1 receptor accessory protein; LSC, leukaemic stem cell; MDS, myelodysplastic syndrome; mTOR, mechanistic target of rapamycin; N/A, not available; NF-jB, nuclear factor kappa B.…”

Section: Opportunities For Therapeutic Intervention and Future Directmentioning

confidence: 99%

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Energy metabolism and drug response in myeloid leukaemic stem cells

et al. 2019

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Summary Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.

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Section: Opportunities For Therapeutic Intervention and Future Directmentioning

confidence: 99%

Section: Opportunities For Therapeutic Intervention and Future Directmentioning

confidence: 99%

Energy metabolism and drug response in myeloid leukaemic stem cells

et al. 2019

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“…Phosphorylated STATs then binds to specific DNA elements and activates gene transcription (Murray, 2014). Specifically, the JAK2/STAT3 signaling pathway plays crucial roles in the EMT, apoptosis, proliferation, and drug resistance of various cancers (B. Li & Huang, 2017; Yu, Gong, Li, Pan, & Zhang, 2018), and the activation of STAT3 is closely related to the stemness of cancer cells (Kuepper et al, 2019; Shiraiwa et al, 2019). However, whether the JAK2/STAT3 pathway regulates EMT and the stemness of OSCC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway

Chen

Shao

Jiang

et al. 2020

Journal Cellular Physiology

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Chemokines and their receptors show a strong relationship with poor clinical outcomes in various cancers. However, their underlying mechanisms remain to be fully elucidated. In our research, we found C-C chemokine receptor 7 (CCR7) and its ligand chemokine ligand 21 (CCL21) were abnormally abundant in oral squamous cell carcinoma (OSCC) tissues, and CCR7 expression was correlated with poor prognosis of OSCC. After exogenous CCL21 stimulation, epithelial-mesenchymal transition (EMT) was promoted in OSCC cells, and cancer stem cell-related markers CD133, CD44, BMI1, ALDH1A1, and OCT4 increased. The migration, invasion, tumorsphere formation, and colony formation abilities of OSCC cells were enhanced, indicating that the stemness of OSCC cells was also improved. The knockdown and overexpression of CCR7 efficiently affected the CCL21-induced EMT and stemness of OSCC cells. When treated with CCL21, the phospho-JAK2 and phospho-STAT3 markedly increased. The inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) significantly suppressed CCL21-induced EMT and stemness of OSCC cells. In conclusion, CCL21/CCR7 axis regulated EMT progress and promoted the stemness of OSCC by activating the JAK2/STAT3 signaling pathway. CCL21/CCR7 might be an effective target for OSCC prevention and treatment.

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“…Among many others, targeting JAK/STAT, IL-1, p53/ MYC signaling, or metabolic activity has recently been shown to impair LSC survival [12][13][14][15][16]. Eventually, these observations have given rise to clinical trials, but successful implementation into routine clinical application could not be achieved so far.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

et al. 2020

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Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

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Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling

Cited by 39 publications

References 67 publications

Energy metabolism and drug response in myeloid leukaemic stem cells

Energy metabolism and drug response in myeloid leukaemic stem cells

CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway

Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

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